rs397517019
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The ENST00000340811.9(PKP2):c.214G>T(p.Val72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000391 in 1,532,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
ENST00000340811.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.214G>T | p.Val72Leu | missense_variant | 1/13 | ENST00000340811.9 | NP_001005242.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.214G>T | p.Val72Leu | missense_variant | 1/13 | 1 | NM_001005242.3 | ENSP00000342800 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000563 AC: 1AN: 177540Hom.: 0 AF XY: 0.0000100 AC XY: 1AN XY: 99890
GnomAD4 exome AF: 0.00000362 AC: 5AN: 1380746Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 2AN XY: 683514
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74228
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 10, 2018 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Arrhythmogenic right ventricular dysplasia 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 18, 2022 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the PKP2 protein (p.Val72Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 45061). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 02, 2023 | This missense variant replaces valine with leucine at codon 72 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 1/177540 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This missense variant replaces valine with leucine at codon 72 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has been identified in 1/177540 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at