rs281865142
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PVS1_StrongPP5BS2
The NM_001289808.2(CRYAB):c.343del(p.Ser115ProfsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000991 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S115S) has been classified as Uncertain significance.
Frequency
Consequence
NM_001289808.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAB | NM_001289808.2 | c.343del | p.Ser115ProfsTer14 | frameshift_variant | 3/3 | ENST00000650687.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAB | ENST00000650687.2 | c.343del | p.Ser115ProfsTer14 | frameshift_variant | 3/3 | NM_001289808.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250916Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135704
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727236
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74312
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 08, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 09, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation, as the last 61 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Published functional studies demonstrate a damaging effect as induced pluripotent stem cells (iPSC) derived from fibroblasts from an infant with myofibrillar myopathy showed that this variant causes protein insolubility, resulting in the loss of alpha-B-crystallin protein expression in iPSC-derived skeletal myotubes and cardiomyocytes (Mitzelfelt et al., 2016); Reported in ClinVar (ClinVar Variant ID# 38963; Landrum et al., 2016); While other truncating variants in the CRYAB gene have been reported in HGMD in association with autosomal recessive infantile myofibrillar myopathy (Stenson et al., 2014), only one truncating variant has been previously reported in association with autosomal dominant cardiomyopathy (Jensen et al. 2013).; This variant is associated with the following publications: (PMID: 21130652, 27226619, 31534214) - |
Dilated cardiomyopathy 1II Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | This sequence change creates a premature translational stop signal (p.Ser115Profs*14) in the CRYAB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the CRYAB protein. This variant is present in population databases (rs281865142, gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive myofibrillar myopathy (PMID: 21130652, 27226619). ClinVar contains an entry for this variant (Variation ID: 38963). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CRYAB function (PMID: 21130652, 27226619). For these reasons, this variant has been classified as Pathogenic. - |
Myofibrillar myopathy 2;C3554649:Dilated cardiomyopathy 1II;C3808377:Cataract 16 multiple types;C5190691:Fatal infantile hypertonic myofibrillar myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 27, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The c.343delT (p.S115Pfs*14) alteration, located in exon 3 (coding exon 3) of the CRYAB gene, consists of a deletion of one nucleotide at position 343, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Myofibrillar myopathy 2 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at