rs533659697
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting
The NM_001005242.3(PKP2):āc.1796A>Gā(p.Lys599Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,140 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. K599E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001005242.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1796A>G | p.Lys599Arg | missense_variant | 8/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1796A>G | p.Lys599Arg | missense_variant | 8/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251342Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135856
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727214
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152324Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2AN XY: 74498
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 643 of the PKP2 protein (p.Lys643Arg). This variant is present in population databases (rs533659697, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 464416). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 20, 2017 | The p.Lys643Arg variant (rs533659697) has not been reported in the medical literature and is not listed in gene-specific variant databases. It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in East Asian populations of 0.03% (identified in 6 out of 17,242 chromosomes). The lysine at codon 643 is moderately conserved considering 8 species (Alamut software v2.9), and computational analyses suggest this variant does not have a significant effect on PKP2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Lys643Arg variant cannot be determined with certainty. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 15, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 04, 2024 | 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