rs74315439
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000394.4(CRYAA):c.346C>T(p.Arg116Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116H) has been classified as Pathogenic.
Frequency
Consequence
NM_000394.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAA | NM_000394.4 | c.346C>T | p.Arg116Cys | missense_variant | 3/3 | ENST00000291554.6 | |
CRYAA | NM_001363766.1 | c.235C>T | p.Arg79Cys | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAA | ENST00000291554.6 | c.346C>T | p.Arg116Cys | missense_variant | 3/3 | 1 | NM_000394.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD4 exome Cov.: 0
GnomAD4 genome Cov.: 0
ClinVar
Submissions by phenotype
Cataract 9 multiple types Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 30, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg116 amino acid residue in CRYAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18302245, 20079887, 22045060, 22216983). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CRYAA function (PMID: 10684623, 11123904, 18085469, 22045060, 22140512, 22347476). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRYAA protein function. ClinVar contains an entry for this variant (Variation ID: 16957). This missense change has been observed in individual(s) with autosomal dominant congenital cataract (PMID: 9467006, 16735993, 17296897). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 116 of the CRYAA protein (p.Arg116Cys). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2007 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at