rs543233804
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001005242.3(PKP2):c.2234T>C(p.Ile745Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,928 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I745V) has been classified as Likely benign.
Frequency
Consequence
NM_001005242.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.2234T>C | p.Ile745Thr | missense_variant | 11/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.2234T>C | p.Ile745Thr | missense_variant | 11/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251426Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135884
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461692Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727168
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74450
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 789 of the PKP2 protein (p.Ile789Thr). This variant is present in population databases (rs543233804, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of PKP2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 575611). 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 threonine 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. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces isoleucine with threonine at codon 789 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 not been identified 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2022 | This missense variant replaces isoleucine with threonine at codon 789 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 not been identified 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 575611; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2021 | The p.I789T variant (also known as c.2366T>C), located in coding exon 12 of the PKP2 gene, results from a T to C substitution at nucleotide position 2366. The isoleucine at codon 789 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at