Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11438989, 10411676, 9326320, 26453610, 27499327, 26147798)
ClinVar Genomic variation as it relates to human health
NM_000297.4(PKD2):c.709+1G>A
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
5 out of 6 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
6
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000297.4(PKD2):c.709+1G>A
Variation ID: 92797 Accession: VCV000092797.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q22.1 4: 88019572 (GRCh38) [ NCBI UCSC ] 4: 88940724 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 29, 2015 Apr 13, 2025 Jul 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000297.4:c.709+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000004.12:g.88019572G>A NC_000004.11:g.88940724G>A NG_008604.1:g.16905G>A - Protein change
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- Other names
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- Canonical SPDI
- NC_000004.12:88019571:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| PKD2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1111 | 1427 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 10, 2023 | RCV000078584.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001292113.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
May 24, 2023 | RCV003584550.3 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 17, 2023 | RCV002470757.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Feb 10, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004025432.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is … (more)
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11438989, 10411676, 9326320, 26453610, 27499327, 26147798) (less)
|
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Likely pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 2
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005416397.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PM2_Supporting+PVS1_Strong+PS4_Supporting+PP4
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Likely pathogenic
(May 24, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant polycystic kidney disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293199.2
First in ClinVar: Feb 14, 2024 Last updated: Mar 04, 2025 |
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional … (more)
This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 92797). Disruption of this splice site has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 9326320, 26453610, 27499327, 33437033). This sequence change affects a donor splice site in intron 2 of the PKD2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). (less)
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Pathogenic
(Dec 18, 2012)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110440.9
First in ClinVar: Jan 17, 2014 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
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Pathogenic
(Jul 17, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Polycystic kidney disease 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768756.2
First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 2 (MIM#613095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with autosomal dominant polycystic kidney disease (PMIDs: 9326320, 27499327, 26453610, 28356211, 32457805) and classified as pathogenic by diagnostic laboratories (ClinVar, ADPKD database). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
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Polycystic Kidney disease
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001480945.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
The PKD2 c.709+1G>A variant was identified in 3 of 1910 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Audrézet 2012, Hwang 2016, Veldhuisen … (more)
The PKD2 c.709+1G>A variant was identified in 3 of 1910 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Audrézet 2012, Hwang 2016, Veldhuisen 1997). The variant was also identified in dbSNP (ID: rs398123308) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by ClinVar), the ClinVar database (classified as pathogenic by Emory Genetics), and the ADPKD Mutation Database (classified as definitely pathogenic). The variant was not found in 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8th 2016). The c.709+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
Comment:
Comment:
PM2_Supporting+PVS1_Strong+PS4_Supporting+PP4
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 92797). Disruption of this splice site has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 9326320, 26453610, 27499327, 33437033). This sequence change affects a donor splice site in intron 2 of the PKD2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 2 (MIM#613095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with autosomal dominant polycystic kidney disease (PMIDs: 9326320, 27499327, 26453610, 28356211, 32457805) and classified as pathogenic by diagnostic laboratories (ClinVar, ADPKD database). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The PKD2 c.709+1G>A variant was identified in 3 of 1910 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Audrézet 2012, Hwang 2016, Veldhuisen 1997). The variant was also identified in dbSNP (ID: rs398123308) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by ClinVar), the ClinVar database (classified as pathogenic by Emory Genetics), and the ADPKD Mutation Database (classified as definitely pathogenic). The variant was not found in 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8th 2016). The c.709+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11438989, 10411676, 9326320, 26453610, 27499327, 26147798)
Comment:
PM2_Supporting+PVS1_Strong+PS4_Supporting+PP4
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 92797). Disruption of this splice site has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 9326320, 26453610, 27499327, 33437033). This sequence change affects a donor splice site in intron 2 of the PKD2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 2 (MIM#613095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with autosomal dominant polycystic kidney disease (PMIDs: 9326320, 27499327, 26453610, 28356211, 32457805) and classified as pathogenic by diagnostic laboratories (ClinVar, ADPKD database). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The PKD2 c.709+1G>A variant was identified in 3 of 1910 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Audrézet 2012, Hwang 2016, Veldhuisen 1997). The variant was also identified in dbSNP (ID: rs398123308) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by ClinVar), the ClinVar database (classified as pathogenic by Emory Genetics), and the ADPKD Mutation Database (classified as definitely pathogenic). The variant was not found in 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8th 2016). The c.709+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing. | Mallawaarachchi AC | European journal of human genetics : EJHG | 2021 | PMID: 33437033 |
| Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families. | Mantovani V | Frontiers in genetics | 2020 | PMID: 32457805 |
| PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis. | Cornec-Le Gall E | American journal of kidney diseases : the official journal of the National Kidney Foundation | 2017 | PMID: 28356211 |
| Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). | Carrera P | Scientific reports | 2016 | PMID: 27499327 |
| Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease. | Hwang YH | Journal of the American Society of Nephrology : JASN | 2016 | PMID: 26453610 |
| Clinical utility of PKD2 mutation testing in a polycystic kidney disease cohort attending a specialist nephrology out-patient clinic. | Robinson C | BMC nephrology | 2012 | PMID: 22863349 |
| Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. | Rossetti S | Journal of the American Society of Nephrology : JASN | 2007 | PMID: 17582161 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2). | Veldhuisen B | American journal of human genetics | 1997 | PMID: 9326320 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKD2 | - | - | - | - |
Text-mined citations for rs398123308 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 17, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.