chr6-121446911-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_000165.5(GJA1):c.64G>A(p.Gly22Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000165.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.64G>A | p.Gly22Arg | missense_variant | Exon 2 of 2 | ENST00000282561.4 | NP_000156.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJA1 | ENST00000282561.4 | c.64G>A | p.Gly22Arg | missense_variant | Exon 2 of 2 | 1 | NM_000165.5 | ENSP00000282561.3 | ||
GJA1 | ENST00000647564.1 | c.64G>A | p.Gly22Arg | missense_variant | Exon 2 of 2 | ENSP00000497565.1 | ||||
GJA1 | ENST00000649003.1 | c.64G>A | p.Gly22Arg | missense_variant | Exon 2 of 2 | ENSP00000497283.1 | ||||
GJA1 | ENST00000650427.1 | c.64G>A | p.Gly22Arg | missense_variant | Exon 2 of 2 | ENSP00000497367.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Oculodentodigital dysplasia, autosomal recessive Pathogenic:1
This sequence change replaces glycine with arginine at codon 22 of the GJA1 protein (p.Gly22Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant disrupts the p.Gly22 amino acid residue in GJA1. Other variant(s) that disrupt this residue have been observed in individuals with GJA1-related conditions (PMID: 12457340), which suggests that this may be a clinically significant amino acid residue. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with oculodentodigital dysplasia (ODDD) (Invitae), and this variant has been reported in an unrelated individual with this condition (PMID: 19338053). 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. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at