rs886041410
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000496.3(CRYBB2):c.563G>A(p.Arg188His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R188L) has been classified as Pathogenic.
Frequency
Consequence
NM_000496.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYBB2 | NM_000496.3 | c.563G>A | p.Arg188His | missense_variant | 6/6 | ENST00000398215.3 | |
CRYBB2 | XM_006724141.4 | c.563G>A | p.Arg188His | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYBB2 | ENST00000398215.3 | c.563G>A | p.Arg188His | missense_variant | 6/6 | 1 | NM_000496.3 | P1 | |
CRYBB2 | ENST00000651629.1 | c.563G>A | p.Arg188His | missense_variant | 6/6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Cataract 3 multiple types Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 188 of the CRYBB2 protein (p.Arg188His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with nonsyndromic congenital cataract (PMID: 22312185, 32498547). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280142). 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. Experimental studies have shown that this missense change affects CRYBB2 function (PMID: 24120835, 24704203). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 25, 2019 | Published functional studies demonstrate that the R188H variant perturbs the -crystallin oligomeric equilibrium, leading to increased aggregation and decreased stability of B2-crystallin ( Zhang et al., 2014).; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24704203, 22312185, 24120835, 32498547) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at