rs782316391
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001289808.2(CRYAB):c.65G>A(p.Arg22His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,608,564 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 (★★).
Frequency
Consequence
NM_001289808.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CRYAB | NM_001289808.2 | c.65G>A | p.Arg22His | missense_variant | Exon 1 of 3 | ENST00000650687.2 | NP_001276737.1 | |
CRYAB | NM_001289807.1 | c.65G>A | p.Arg22His | missense_variant | Exon 2 of 4 | NP_001276736.1 | ||
CRYAB | NM_001368245.1 | c.65G>A | p.Arg22His | missense_variant | Exon 2 of 4 | NP_001355174.1 | ||
CRYAB | NM_001885.3 | c.65G>A | p.Arg22His | missense_variant | Exon 2 of 4 | NP_001876.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151898Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000167 AC: 4AN: 238858Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 128820
GnomAD4 exome AF: 0.0000240 AC: 35AN: 1456666Hom.: 0 Cov.: 31 AF XY: 0.0000304 AC XY: 22AN XY: 723894
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151898Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74176
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1II Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 22 of the CRYAB protein (p.Arg22His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CRYAB-related conditions. ClinVar contains an entry for this variant (Variation ID: 569482). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Myofibrillar myopathy 2;C3554649:Dilated cardiomyopathy 1II;C3808377:Cataract 16 multiple types;C5190691:Fatal infantile hypertonic myofibrillar myopathy Uncertain:1
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not provided Uncertain:1
Has not been published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#569482; Marcos et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32420686) -
Cardiovascular phenotype Uncertain:1
The p.R22H variant (also known as c.65G>A), located in coding exon 1 of the CRYAB gene, results from a G to A substitution at nucleotide position 65. The arginine at codon 22 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at