1-197421870-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_201253.3(CRB1):c.2042G>A(p.Cys681Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,878 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C681W) has been classified as Uncertain significance.
Frequency
Consequence
NM_201253.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRB1 | NM_201253.3 | c.2042G>A | p.Cys681Tyr | missense_variant | 6/12 | ENST00000367400.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRB1 | ENST00000367400.8 | c.2042G>A | p.Cys681Tyr | missense_variant | 6/12 | 1 | NM_201253.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251086Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135678
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461878Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2017 | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Leber congenital amaurosis 8 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 29, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Leber congenital amaurosis Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 04, 2020 | - - |
Retinitis pigmentosa 12;C3151202:Leber congenital amaurosis 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 11, 2023 | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CRB1 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 99874). This missense change has been observed in individual(s) with CRB1-related conditions (PMID: 17525851, 24265693, 30576320, 32865313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs62636266, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 681 of the CRB1 protein (p.Cys681Tyr). - |
Retinitis pigmentosa 12 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at