rs183487020
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4
The NM_000275.3(OCA2):c.593C>T(p.Pro198Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P198P) has been classified as Likely benign.
Frequency
Consequence
NM_000275.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OCA2 | NM_000275.3 | c.593C>T | p.Pro198Leu | missense_variant | 6/24 | ENST00000354638.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.593C>T | p.Pro198Leu | missense_variant | 6/24 | 1 | NM_000275.3 | P1 | |
OCA2 | ENST00000353809.9 | c.593C>T | p.Pro198Leu | missense_variant | 6/23 | 1 | |||
OCA2 | ENST00000431101.1 | c.593C>T | p.Pro198Leu | missense_variant | 6/7 | 3 | |||
OCA2 | ENST00000445578.5 | c.573+2291C>T | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000342 AC: 52AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251266Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135858
GnomAD4 exome AF: 0.0000595 AC: 87AN: 1461454Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727062
GnomAD4 genome ? AF: 0.000341 AC: 52AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29AN XY: 74482
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2023 | 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: 32552135, 22995991, 12713581, 30609409, 25919014, 19865097, 18821858, 24118800, 31196117, 34838614) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the OCA2 protein (p.Pro198Leu). This variant is present in population databases (rs183487020, gnomAD 0.1%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 19865097, 25919014, 29437493; Invitae). ClinVar contains an entry for this variant (Variation ID: 198063). 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 not expected to disrupt OCA2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Tyrosinase-positive oculocutaneous albinism Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OCA2 related disorder (ClinVar ID: VCV000198063, PMID:12713581, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88, PP3_P). A missense variant is a common mechanism associated with Albinism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000124, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 27, 2017 | The p.Pro198Leu (NM_000275.2 c.593C>T) variant in OCA2 has been reported in at l east 1 homozygous, 2 compound heterozygous and 1 heterozygous individuals of Tur kish, Chinese and Japanese ancestry with oculocutaneous albinism II (Rooryck 200 8, Suzuki 2003, Wang 2015, and Wei 2010). This variant has also been reported in ClinVar (Variation ID# 198063). This variant has been identified in 0.12% (13/1 0222) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs183487020). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a r ecessive carrier frequency. Computational prediction tools and conservation anal ysis suggest that the p.Pro198Leu variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, altho ugh additional studies are required to fully establish its clinical significance , the p.Pro198Leu variant is likely pathogenic based upon its biallelic observat ions in multiple affected individuals and low population frequency. - |
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at