rs138538072
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The ENST00000070846.11(PKP2):c.1420G>A(p.Ala474Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,337,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A474V) has been classified as Likely benign.
Frequency
Consequence
ENST00000070846.11 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1379-2067G>A | intron_variant | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1379-2067G>A | intron_variant | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000651 AC: 99AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000184 AC: 45AN: 244150Hom.: 0 AF XY: 0.000174 AC XY: 23AN XY: 132430
GnomAD4 exome AF: 0.000103 AC: 122AN: 1185308Hom.: 0 Cov.: 21 AF XY: 0.0000950 AC XY: 56AN XY: 589318
GnomAD4 genome ? AF: 0.000644 AC: 98AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74436
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 19, 2022 | Variant summary: PKP2 c.1420G>A (p.Ala474Thr) 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 0.00018 in 244150 control chromosomes, predominantly at a frequency of 0.0024 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKP2 causing Arrhythmia phenotype (0.00043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1420G>A has been reported in the literature in individuals affected with dilated cardiomyopathy (Pugh_2014, Burstein_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 17, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Ala474Thr varia nt in PKP2 has been identified in 7/3738 African American chromosomes from a bro ad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs138538072). Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, and PolyPhen2) suggest that the Ala474Thr varian t may not impact the protein, though this information is not predictive enough t o rule out pathogenicity. This data supports that the Ala474Thr variant may be b enign but is insufficient to rule out a role in disease. Additional studies are needed to fully assess its clinical significance. - |
Cardiomyopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 30, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 04, 2019 | - - |
Arrhythmogenic right ventricular dysplasia 9 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Arrhythmogenic right ventricular cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
PKP2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 12, 2022 | 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). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PKP2: BP4 - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at