chr11-111908924-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_001289808.2(CRYAB):c.368G>A(p.Arg123Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R123W) has been classified as Likely benign.
Frequency
Consequence
NM_001289808.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152050Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251306Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135842
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727240
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74274
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Arg123Gln variant in CRYAB has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/16496 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, the clinical significan ce of the p.Arg123Gln variant is uncertain. -
Dilated cardiomyopathy 1II Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 123 of the CRYAB protein (p.Arg123Gln). This variant is present in population databases (rs782206421, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal dominant CRYAB-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 228541). 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. -
not provided Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.R123Q variant (also known as c.368G>A), located in coding exon 3 of the CRYAB gene, results from a G to A substitution at nucleotide position 368. The arginine at codon 123 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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