This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_000297.4(PKD2):c.2411G>A (p.Ser804Asn)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(4); Likely benign(1)
Uncertain significance(2); Benign(4); Likely benign(1)
7 out of 10 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.
10
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000297.4(PKD2):c.2411G>A (p.Ser804Asn)
Variation ID: 289403 Accession: VCV000289403.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4q22.1 4: 88067950 (GRCh38) [ NCBI UCSC ] 4: 88989102 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 6, 2016 May 25, 2025 Feb 3, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000297.4:c.2411G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000288.1:p.Ser804Asn missense NR_156488.2:n.2389G>A non-coding transcript variant NC_000004.12:g.88067950G>A NC_000004.11:g.88989102G>A NG_008604.1:g.65283G>A - Protein change
- S804N
- Other names
- -
- Canonical SPDI
- NC_000004.12:88067949:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00260 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00083
The Genome Aggregation Database (gnomAD), exomes 0.00085
1000 Genomes Project 0.00260
The Genome Aggregation Database (gnomAD) 0.00261
The Genome Aggregation Database (gnomAD) 0.00280
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00284
Trans-Omics for Precision Medicine (TOPMed) 0.00297
1000 Genomes Project 30x 0.00312
- 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. |
|||
| PKD2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1104 | 1419 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 1, 2023 | RCV000755622.29 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 31, 2020 | RCV000405309.9 | |
| Conflicting classifications of pathogenicity (2) |
criteria provided, conflicting classifications
|
Oct 21, 2022 | RCV001157152.8 | |
| Benign (1) |
criteria provided, single submitter
|
Feb 3, 2025 | RCV001084804.10 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001292453.3 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Sep 12, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604829.2
First in ClinVar: Dec 06, 2016 Last updated: Feb 17, 2019 |
|
|
|
Uncertain significance
(Apr 27, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001318699.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Benign
(Dec 31, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001879479.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
|
Benign
(Feb 03, 2025)
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: SCV000658972.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 25, 2025 |
|
|
|
Benign
(Jul 11, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000343762.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Benign
(Apr 01, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004152960.14
First in ClinVar: Nov 20, 2023 Last updated: May 25, 2025 |
Comment:
PKD2: BS1, BS2
Number of individuals with the variant: 1
|
|
|
Likely benign
(Oct 21, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Polycystic kidney disease 2
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003839043.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
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: SCV001480999.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
The PKD2 p.Ser804Asn variant was identified in 1 of 404 proband chromosomes (frequency: 0.0025) from individuals or families with Autosomal Dominant PKD (Rossetti 2007). The … (more)
The PKD2 p.Ser804Asn variant was identified in 1 of 404 proband chromosomes (frequency: 0.0025) from individuals or families with Autosomal Dominant PKD (Rossetti 2007). The variant was also identified in dbSNP (ID: rs145343957) as “With other allele”, in ClinVar (as benign by EGL Genetic Diagnostics and Invitae, and as uncertain significance by ARUP Laboratories), LOVD 3.0 (1x as "indeterminate"), and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 277 of 276842 chromosomes (1 homozygous) at a frequency of 0.001001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 179 of 24034 chromosomes (freq: 0.007), Other in 17 of 6460 chromosomes (freq: 0.003), Latino in 65 of 34394 chromosomes (freq: 0.002), European (Non-Finnish) in 16 of 126422 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The mutation is located within the consensus kinase recognition sequence; a functional study showed the p.Ser804Asn variant abolished Ser801 phosphorylation, indicating its likely physiological significance, and this study therefore classified the variant as pathogenic (Streets 2010). The p.Ser804 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035381.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002038311.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
|
|
Comment:
Comment:
PKD2: BS1, BS2
Comment:
The PKD2 p.Ser804Asn variant was identified in 1 of 404 proband chromosomes (frequency: 0.0025) from individuals or families with Autosomal Dominant PKD (Rossetti 2007). The variant was also identified in dbSNP (ID: rs145343957) as “With other allele”, in ClinVar (as benign by EGL Genetic Diagnostics and Invitae, and as uncertain significance by ARUP Laboratories), LOVD 3.0 (1x as "indeterminate"), and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 277 of 276842 chromosomes (1 homozygous) at a frequency of 0.001001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 179 of 24034 chromosomes (freq: 0.007), Other in 17 of 6460 chromosomes (freq: 0.003), Latino in 65 of 34394 chromosomes (freq: 0.002), European (Non-Finnish) in 16 of 126422 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The mutation is located within the consensus kinase recognition sequence; a functional study showed the p.Ser804Asn variant abolished Ser801 phosphorylation, indicating its likely physiological significance, and this study therefore classified the variant as pathogenic (Streets 2010). The p.Ser804 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
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:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
PKD2: BS1, BS2
Comment:
The PKD2 p.Ser804Asn variant was identified in 1 of 404 proband chromosomes (frequency: 0.0025) from individuals or families with Autosomal Dominant PKD (Rossetti 2007). The variant was also identified in dbSNP (ID: rs145343957) as “With other allele”, in ClinVar (as benign by EGL Genetic Diagnostics and Invitae, and as uncertain significance by ARUP Laboratories), LOVD 3.0 (1x as "indeterminate"), and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 277 of 276842 chromosomes (1 homozygous) at a frequency of 0.001001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 179 of 24034 chromosomes (freq: 0.007), Other in 17 of 6460 chromosomes (freq: 0.003), Latino in 65 of 34394 chromosomes (freq: 0.002), European (Non-Finnish) in 16 of 126422 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The mutation is located within the consensus kinase recognition sequence; a functional study showed the p.Ser804Asn variant abolished Ser801 phosphorylation, indicating its likely physiological significance, and this study therefore classified the variant as pathogenic (Streets 2010). The p.Ser804 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Population data improves variant interpretation in autosomal dominant polycystic kidney disease. | Mallawaarachchi AC | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30369598 |
| 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 |
| A public resource facilitating clinical use of genomes. | Ball MP | Proceedings of the National Academy of Sciences of the United States of America | 2012 | PMID: 22797899 |
| Neonatal onset autosomal dominant polycystic kidney disease (ADPKD) in a patient homozygous for a PKD2 missense mutation due to uniparental disomy. | Losekoot M | Journal of medical genetics | 2012 | PMID: 22114106 |
| Protein kinase D-mediated phosphorylation of polycystin-2 (TRPP2) is essential for its effects on cell growth and calcium channel activity. | Streets AJ | Molecular biology of the cell | 2010 | PMID: 20881056 |
| Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. | Rossetti S | Journal of the American Society of Nephrology : JASN | 2007 | PMID: 17582161 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PKD2 | - | - | - | - |
| http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=4&from=88989102&to=88989102 | - | - | - | - |
Text-mined citations for rs145343957 ...
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 25, 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.