chr22-26599552-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_001887.4(CRYBB1):c.697C>T(p.Arg233Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,014 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R233H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001887.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYBB1 | NM_001887.4 | c.697C>T | p.Arg233Cys | missense_variant | 6/6 | ENST00000647684.1 | |
CRYBB1 | XM_011529899.4 | c.697C>T | p.Arg233Cys | missense_variant | 6/6 | ||
CRYBA4 | XM_006724140.4 | c.-239+2469G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYBB1 | ENST00000647684.1 | c.697C>T | p.Arg233Cys | missense_variant | 6/6 | NM_001887.4 | P1 | ||
ENST00000668614.1 | n.56+2469G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152252Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251198Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135834
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461762Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727184
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74388
ClinVar
Submissions by phenotype
Cataract 17 multiple types Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2022 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRYBB1 protein function. This variant has not been reported in the literature in individuals affected with CRYBB1-related conditions. This variant is present in population databases (rs372169881, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 233 of the CRYBB1 protein (p.Arg233Cys). - |
CRYBB1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 26, 2023 | The CRYBB1 c.697C>T variant is predicted to result in the amino acid substitution p.Arg233Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-26995516-G-A). A different nucleotide substitution affecting the same amino acid (p.Arg233His) was reported in the heterozygous state to segregate with congenital cataract in a family (Wang et al. 2011. PubMed ID: 21402992). At this time, the clinical significance of the c.697C>T (p.Arg233Cys) variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at