rs371412500
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4
The NM_000275.3(OCA2):āc.2020C>Gā(p.Leu674Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,614,066 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 33)
Exomes š: 0.00015 ( 1 hom. )
Consequence
OCA2
NM_000275.3 missense
NM_000275.3 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 2.46
Genes affected
OCA2 (HGNC:8101): (OCA2 melanosomal transmembrane protein) This gene encodes the human homolog of the mouse p (pink-eyed dilution) gene. The encoded protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine, which is a precursor to melanin synthesis. It is involved in mammalian pigmentation, where it may control skin color variation and act as a determinant of brown or blue eye color. Mutations in this gene result in type 2 oculocutaneous albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP5
Variant 15-27926186-G-C is Pathogenic according to our data. Variant chr15-27926186-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194918.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Pathogenic=2, Likely_pathogenic=2}.
BP4
Computational evidence support a benign effect (MetaRNN=0.112157196). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.2020C>G | p.Leu674Val | missense_variant | Exon 19 of 24 | 1 | NM_000275.3 | ENSP00000346659.3 | ||
OCA2 | ENST00000353809.9 | c.1948C>G | p.Leu650Val | missense_variant | Exon 18 of 23 | 1 | ENSP00000261276.8 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000322 AC: 81AN: 251282Hom.: 1 AF XY: 0.000457 AC XY: 62AN XY: 135802
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GnomAD4 exome AF: 0.000149 AC: 218AN: 1461756Hom.: 1 Cov.: 31 AF XY: 0.000210 AC XY: 153AN XY: 727182
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 20, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in apparent homozygous state in multiple unrelated healthy adult individuals tested at GeneDx and in large population cohorts (Lek et al., 2016); Observed with an additional OCA2 variant in patients with hypomorphic albinism in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (also known as p.L650V using alternate nomenclature; Mondal et al., 2012; Norman et al., 2017); Observed in the apparent homozygous state in a patient with features of ocular albinism in the published literature (Mondal et al., 2012); This variant is associated with the following publications: (PMID: 23970088, 23010199, 28667292) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 29, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 674 of the OCA2 protein (p.Leu674Val). This variant is present in population databases (rs371412500, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of ocular albinism (PMID: 23010199, 28667292; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1948C>G. ClinVar contains an entry for this variant (Variation ID: 194918). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 13, 2023 | - - |
Tyrosinase-positive oculocutaneous albinism Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.032%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OCA2 related disorder (ClinVar ID: VCV000194918 / PMID: 23010199). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 15, 2018 | - - |
Febrile seizure (within the age range of 3 months to 6 years);C0011991:Diarrhea;C0035243:Respiratory tract infection;C0078918:Oculocutaneous albinism;C0700501:Congenital nystagmus;C4314979:Motor delay, mild Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology | Dec 19, 2019 | The c.2020C>G variant is not present in publicly available databases like Exome Variant Server (EVS) however present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a low minor allele frequency (MAF<0.001) including one homozygote. The variant is present in our in-house exome database in heterozygous state (MAF~0.004). The variant was earlier reported to ClinVar (Accession ID: VCV000194918.1) with conflicting interpretation of pathogenicity (likely pathogenic/uncertain significance). In-silico pathogenicity prediction programs Like SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant as likely deleterious, however there are no functional studies performed earlier to prove this. Due to lack of enough evidence and also considering the additional phenotypes observed in this patient along with oculocutaneous albinism and nystagmus, the variant as has been classified as uncertain significance as per ACMG guidelines. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
T;T
Polyphen
D;P
Vest4
MutPred
0.69
.;Gain of helix (P = 0.132);
MVP
MPC
0.48
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at