rs782440692
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_002230.4(JUP):c.794G>A(p.Arg265His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002230.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
JUP | NM_002230.4 | c.794G>A | p.Arg265His | missense_variant | 5/14 | ENST00000393931.8 | NP_002221.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JUP | ENST00000393931.8 | c.794G>A | p.Arg265His | missense_variant | 5/14 | 1 | NM_002230.4 | ENSP00000377508.3 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151986Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251384Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135878
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461830Hom.: 0 Cov.: 46 AF XY: 0.00000275 AC XY: 2AN XY: 727220
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151986Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74222
ClinVar
Submissions by phenotype
Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 02, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 16, 2022 | ClinVar contains an entry for this variant (Variation ID: 212751). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This missense change has been observed in individual(s) with clinical features of Naxos disease (PMID: 21668431). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 265 of the JUP protein (p.Arg265His). This variant is present in population databases (rs782440692, gnomAD 0.004%). - |
Naxos disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2011 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2023 | The p.R265H variant (also known as c.794G>A), located in coding exon 4 of the JUP gene, results from a G to A substitution at nucleotide position 794. The arginine at codon 265 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as homozygous in two affected family members with arrhythmogenic right ventricular cardiomyopathy, alopecia, and palmoplantar keratoderma (Erken H et al. Br J Dermatol, 2011 Oct;165:917-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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