rs141949212
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong
The NM_000275.3(OCA2):c.2339G>A(p.Gly780Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,612,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000275.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
OCA2 | NM_000275.3 | c.2339G>A | p.Gly780Asp | missense_variant, splice_region_variant | 23/24 | ENST00000354638.8 | NP_000266.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.2339G>A | p.Gly780Asp | missense_variant, splice_region_variant | 23/24 | 1 | NM_000275.3 | ENSP00000346659 | P1 | |
OCA2 | ENST00000353809.9 | c.2267G>A | p.Gly756Asp | missense_variant, splice_region_variant | 22/23 | 1 | ENSP00000261276 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 151992Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251398Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1460816Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726866
GnomAD4 genome AF: 0.000184 AC: 28AN: 151992Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74228
ClinVar
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 10, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | This missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). The variant is in trans with NM_000275.3:c.2360C>T. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000436090). A different missense change at the same codon (p.Gly780Ser) has been reported to be associated with OCA2-related disorder (PMID: 32741191). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 24, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 08, 2022 | PM2, PM3_Strong, PP3 - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 780 of the OCA2 protein (p.Gly780Asp). This variant is present in population databases (rs141949212, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of ocular albinism and/or oculocutaneous albinism (PMID: 28041643, 28976636, 29345414; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 436090). 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. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2024 | 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: 28041643, 28976636, 32581362, 31589614, 34838614, 29345414) - |
Oculocutaneous albinism Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2023 | Variant summary: OCA2 c.2339G>A (p.Gly780Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251398 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (4e-05 vs 0.0043), allowing no conclusion about variant significance. c.2339G>A has been reported in the literature in multiple bi-allelic individuals affected with Oculocutaneous Albinism (example: Lasseaux_OCA2_PCMR_2018). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 29345414). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 04, 2024 | - - |
OCA2-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 30, 2024 | The OCA2 c.2339G>A variant is predicted to result in the amino acid substitution p.Gly780Asp. This variant has been reported in individuals with oculocutaneous albinism (Table S2, patient G004719, Carss et al. 2017. PubMed ID: 28041643; Marti et al. 2018. PubMed ID: 28976636; Table S3, Lasseaux et al. 2018. PubMed ID: 29345414). Additionally, at PreventionGenetics, we have identified this variant, along with a second pathogenic OCA2 variant in at least six unrelated patients with oculocutaneous albinism. This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD, and has been classified as likely pathogenic and pathogenic by numerous labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/436090/). Given the evidence, we interpret c.2339G>A (p.Gly780Asp) as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2018 | - - |
Albinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 10, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at