rs41529845
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000275.3(OCA2):c.1138G>C(p.Val380Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V380M) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
OCA2
NM_000275.3 missense
NM_000275.3 missense
Scores
2
10
5
Clinical Significance
Conservation
PhyloP100: 6.96
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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OCA2 | NM_000275.3 | c.1138G>C | p.Val380Leu | missense_variant | 11/24 | ENST00000354638.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.1138G>C | p.Val380Leu | missense_variant | 11/24 | 1 | NM_000275.3 | P1 | |
OCA2 | ENST00000353809.9 | c.1066G>C | p.Val356Leu | missense_variant | 10/23 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251406Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727218
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GnomAD4 genome ? AF: 0.000164 AC: 25AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 380 of the OCA2 protein (p.Val380Leu). This variant is present in population databases (rs41529845, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with OCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1391787). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
0.55
.;Gain of catalytic residue at V380 (P = 0.0088);
MVP
MPC
0.17
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at