rs1203386884
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_004076.5(CRYBB3):c.466G>A(p.Gly156Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,150 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G156E) has been classified as Pathogenic.
Frequency
Consequence
NM_004076.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYBB3 | NM_004076.5 | c.466G>A | p.Gly156Arg | missense_variant | 5/6 | ENST00000215855.7 | |
CRYBB3 | XM_047441147.1 | c.466G>A | p.Gly156Arg | missense_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYBB3 | ENST00000215855.7 | c.466G>A | p.Gly156Arg | missense_variant | 5/6 | 1 | NM_004076.5 | P1 | |
CRYBB3 | ENST00000404334.1 | c.327+1463G>A | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74326
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2023 | 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; This variant is associated with the following publications: (PMID: 35011756, 33494148, 33510601, 27307692, 34014271, 32830442) - |
Cataract 22 multiple types Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly156 amino acid residue in CRYBB3. Other variant(s) that disrupt this residue have been observed in individuals with CRYBB3-related conditions (PMID: 34356085), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 534700). This missense change has been observed in individual(s) with autosomal dominant congenital cataract (PMID: 27307692, 32830442, 33510601, 34014271). In at least one individual the variant was observed to be de novo. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 156 of the CRYBB3 protein (p.Gly156Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at