rs104893964
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000165.5(GJA1):c.65G>A(p.Gly22Glu) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G22R) has been classified as Pathogenic.
Frequency
Consequence
NM_000165.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.65G>A | p.Gly22Glu | missense_variant | 2/2 | ENST00000282561.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJA1 | ENST00000282561.4 | c.65G>A | p.Gly22Glu | missense_variant | 2/2 | 1 | NM_000165.5 | P1 | |
GJA1 | ENST00000647564.1 | c.65G>A | p.Gly22Glu | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000649003.1 | c.65G>A | p.Gly22Glu | missense_variant | 2/2 | P1 | |||
GJA1 | ENST00000650427.1 | c.65G>A | p.Gly22Glu | missense_variant | 2/2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Oculodentodigital dysplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
Oculodentodigital dysplasia, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 06, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 22 of the GJA1 protein (p.Gly22Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with oculodentodigital dysplasia (ODDD) (PMID: 19338053, 32318302). ClinVar contains an entry for this variant (Variation ID: 16985). 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. This variant disrupts the p.Gly22 amino acid residue in GJA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19338053; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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