12-32868967-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_001005242.3(PKP2):āc.1130T>Cā(p.Ile377Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I377V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001005242.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1130T>C | p.Ile377Thr | missense_variant | 4/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1130T>C | p.Ile377Thr | missense_variant | 4/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152268Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461580Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727102
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74394
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 9 Uncertain:2
Uncertain significance, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2017 | 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. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 45009). This variant is present in population databases (rs397516985, ExAC 0.01%). This sequence change replaces isoleucine with threonine at codon 377 of the PKP2 protein (p.Ile377Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 25, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Ile377Thr v ariant (PKP2) has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ile377Thr variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. This variant has not been identified in large and broad popu lations by the NHBLI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) . Although computational predictions and absence in the general population suppo rt that the Ile377Thr variant may be pathogenic, additional studies are needed t o fully assess its clinical significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2021 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 45009; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2020 | The c.1130T>C (p.I377T) alteration is located in exon 4 (coding exon 4) of the PKP2 gene. This alteration results from a T to C substitution at nucleotide position 1130, causing the isoleucine (I) at amino acid position 377 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at