ClinVar Genomic variation as it relates to human health
NM_007254.4(PNKP):c.416G>A (p.Arg139His)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(6); Benign(1); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007254.4(PNKP):c.416G>A (p.Arg139His)
Variation ID: 159794 Accession: VCV000159794.56
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 49865209 (GRCh38) [ NCBI UCSC ] 19: 50368466 (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 Nov 23, 2014 Aug 4, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007254.4:c.416G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009185.2:p.Arg139His missense NC_000019.10:g.49865209C>T NC_000019.9:g.50368466C>T NG_027717.1:g.7357G>A - Protein change
- R139H
- Other names
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- Canonical SPDI
- NC_000019.10:49865208:C:T
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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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0.00060 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00207
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00231
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00185
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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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PNKP | - | - |
GRCh38 GRCh37 |
1127 | 1142 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (2) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000147358.17 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Dec 1, 2023 | RCV000433486.44 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 24, 2018 | RCV000515248.11 | |
Benign (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV001086537.15 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 10, 2023 | RCV001815201.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 8, 2019 | RCV002312656.9 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 11, 2021 | RCV003224167.8 | |
PNKP-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Dec 27, 2019 | RCV004532660.1 |
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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Uncertain significance
(Dec 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000203321.7
First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 14
Sex: mixed
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Uncertain significance
(Oct 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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Ataxia - oculomotor apraxia type 4
Microcephaly, seizures, and developmental delay
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898887.1
First in ClinVar: Apr 25, 2019 Last updated: Apr 25, 2019 |
Comment:
PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including … (more)
PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Likely benign
(Oct 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000614683.2
First in ClinVar: Mar 08, 2017 Last updated: Jan 20, 2020 |
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Likely benign
(Apr 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000514214.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
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Uncertain Significance
(Sep 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511621.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Uncertain significance.
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Uncertain significance
(May 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, seizures, and developmental delay
Ataxia - oculomotor apraxia type 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611499.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Likely benign
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Microcephaly, seizures, and developmental delay
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001288754.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Uncertain significance
(Apr 15, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713023.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 4
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Likely benign
(Apr 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000194733.2
First in ClinVar: Nov 23, 2014 Last updated: Jan 29, 2022 |
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Likely benign
(Nov 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 2B2
Ataxia - oculomotor apraxia type 4 Microcephaly, seizures, and developmental delay
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920335.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including … (more)
PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Likely benign
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933878.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: PNKP c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: PNKP c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251392 control chromosomes in the gnomAD database, including 2 homozygotes. To our knowledge, c.416G>A has not been reported in the literature in individuals affected with PNKP-Related Disorders and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23833122, 34009545). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS (n=6), likely benign (n=6), benign (n=1)). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Benign
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 12
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000560526.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(Dec 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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PNKP-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004746961.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Feb 08, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000847273.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.R139H variant (also known as c.416G>A), located in coding exon 3 of the PNKP gene, results from a G to A substitution at nucleotide … (more)
The p.R139H variant (also known as c.416G>A), located in coding exon 3 of the PNKP gene, results from a G to A substitution at nucleotide position 416. The arginine at codon 139 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Likely benign
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001151998.25
First in ClinVar: Feb 03, 2020 Last updated: Aug 04, 2024 |
Comment:
PNKP: BP4, BS2
Number of individuals with the variant: 15
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Uncertain significance
(Dec 12, 2014)
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no assertion criteria provided
Method: research
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Microcephaly, seizures and developmental delay
Affected status: yes
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238400.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The heterozygous variant (c.416G>A; p.Arg139His) in the PNKP gene observed in this patient has not been associated with disease. It occurs at low frequencies in … (more)
The heterozygous variant (c.416G>A; p.Arg139His) in the PNKP gene observed in this patient has not been associated with disease. It occurs at low frequencies in control population (0.2% in ExAC) and a second rare variant was not observed on the other allele. This variant is considered a variant of unknown significance. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders. | Hargreaves CE | Journal of clinical immunology | 2021 | PMID: 34009545 |
Germline missense variants in the BTNL2 gene are associated with prostate cancer susceptibility. | Fitzgerald LM | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2013 | PMID: 23833122 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PNKP | - | - | - | - |
Text-mined citations for rs34472250 ...
HelpRecord last updated Sep 17, 2024
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.