rs144812594
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong
The NM_000275.3(OCA2):c.1211C>T(p.Thr404Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000395 in 1,595,142 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T404T) has been classified as Likely benign.
Frequency
Consequence
NM_000275.3 missense
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 | UniProt |
---|---|---|---|---|---|---|---|
OCA2 | NM_000275.3 | c.1211C>T | p.Thr404Met | missense_variant | 12/24 | ENST00000354638.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.1211C>T | p.Thr404Met | missense_variant | 12/24 | 1 | NM_000275.3 | P1 | |
OCA2 | ENST00000353809.9 | c.1139C>T | p.Thr380Met | missense_variant | 11/23 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000210 AC: 32AN: 152134Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251456Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135906
GnomAD4 exome AF: 0.0000215 AC: 31AN: 1442890Hom.: 0 Cov.: 26 AF XY: 0.0000139 AC XY: 10AN XY: 719260
GnomAD4 genome ? AF: 0.000210 AC: 32AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74440
ClinVar
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 26, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000211766). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Human Genetics, University of Kinshasa | Aug 06, 2022 | This missense variant replaces a conserved Threonine residue with a Methionine. This change is predicted damaging by the vast majority of prediction algorithms. This variant is very rare with no homozygous in gnomAD (AF: 0.0000636), was submitted to ClinVar by multiple submitters mostly classifying this variant as pathogenic/Likely pathogenic (VCV000211766.10), and is mentioned in at least three publications (PMID: 29345414‚ PMID: 10649493). Previous ClinVar submissions contain information regarding functional analysis demonstrating the pathogenic role of this variant. We identified this variant in a heterozygous state in one patient with Tyrosinase-positive oculocutaneous albinism in the Democratic Republic of Congo (DRC). This patient was heterozygous for the classic 2.7 deletion in the OCA2 gene. segregation analysis showed that the variant was in trans to the deletion in our patient. This variant was classified as pathogenic according to the ACMG guidelines - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2023 | Observed as a single heterozygous variant or with a variant of uncertain significance, phase unknown, in patients with oculocutaneous albinism in published literature (Gronskov et al., 2009, Simeonov et al., 2013; Rimoldi et al., 2014); 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: 23824587, 33144682, 24361966, 28266639, 23504663, 27734839, 36116698, 7762554, 34838614, 29345414, 19060277) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 404 of the OCA2 protein (p.Thr404Met). This variant is present in population databases (rs144812594, gnomAD 0.07%). This missense change has been observed in individual(s) with ocular albinism (PMID: 23504663, 24361966, 27734839). 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: 211766). 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 OCA2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 14, 2023 | - - |
OCA2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 28, 2023 | The OCA2 c.1211C>T variant is predicted to result in the amino acid substitution p.Thr404Met. This variant has been reported in the compound heterozygous and homozygous states in individuals with oculocutaneous albinism (OCA) (Rimoldi et al. 2014. PubMed ID: 24361966; Shahzad et al. 2017. PubMed ID: 28266639). This variant has also been reported in a patient with OCA, but a second causative variant was not found (Grønskov et al. 2009. PubMed ID: 19060277, Table 3). At PreventionGenetics, this variant along with a second pathogenic variant has been found in several affected individuals. This variant is classified as likely pathogenic by several independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/211766/). Given the evidence, we classify c.1211C>T (p.Thr404Met) as pathogenic. - |
Nonsyndromic Oculocutaneous Albinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Mar 07, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at