rs146566525
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_001005242.3(PKP2):c.587G>A(p.Arg196His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196C) 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 Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.587G>A | p.Arg196His | missense_variant | 3/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.587G>A | p.Arg196His | missense_variant | 3/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251168Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135778
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461470Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727062
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74322
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 16, 2021 | This sequence change replaces arginine with histidine at codon 196 of the PKP2 protein (p.Arg196His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs146566525, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. 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. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the head domain of the PKP2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/245970 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 27, 2023 | This missense variant replaces arginine with histidine at codon 196 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/251168 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2021 | The p.R196H variant (also known as c.587G>A), located in coding exon 3 of the PKP2 gene, results from a G to A substitution at nucleotide position 587. The arginine at codon 196 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at