rs886039099
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
The NM_001289808.2(CRYAB):āc.324G>Cā(p.Gln108His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_001289808.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CRYAB | NM_001289808.2 | c.324G>C | p.Gln108His | missense_variant, splice_region_variant | 2/3 | ENST00000650687.2 | NP_001276737.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CRYAB | ENST00000650687.2 | c.324G>C | p.Gln108His | missense_variant, splice_region_variant | 2/3 | NM_001289808.2 | ENSP00000499082 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1II Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 108 of the CRYAB protein (p.Gln108His). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). 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: 264247). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 23, 2020 | The p.Q108H variant (also known as c.324G>C), located in coding exon 2 of the CRYAB gene, results from a G to C substitution at nucleotide position 324. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glutamine at codon 108 to histidine, an amino acid with highly similar properties. Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct experimental evidence is unavailable. 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