rs61745150
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4
The NM_000275.3(OCA2):c.1103C>T(p.Ala368Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,980 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: 𝑓 0.00077 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000066 ( 0 hom. )
Consequence
OCA2
NM_000275.3 missense
NM_000275.3 missense
Scores
3
12
4
Clinical Significance
Conservation
PhyloP100: 8.54
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 2 ACMG points.
PM1
?
In a transmembrane_region Helical (size 16) in uniprot entity P_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000275.3
PP5
?
Variant 15-27990589-G-A is Pathogenic according to our data. Variant chr15-27990589-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193574.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=3, Pathogenic=3, not_provided=1}. Variant chr15-27990589-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.054849237). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OCA2 | NM_000275.3 | c.1103C>T | p.Ala368Val | missense_variant | 10/24 | ENST00000354638.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.1103C>T | p.Ala368Val | missense_variant | 10/24 | 1 | NM_000275.3 | P1 | |
OCA2 | ENST00000353809.9 | c.1045-923C>T | intron_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000769 AC: 117AN: 152200Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000215 AC: 54AN: 251112Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135720
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GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461662Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 37AN XY: 727134
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GnomAD4 genome ? AF: 0.000768 AC: 117AN: 152318Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56AN XY: 74478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:4Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 15, 2022 | This OCA2 variant (rs61745150) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African/African American subpopulation (gnomAD: 70/24946 alleles; 0.28%, no homozygotes). This patient's ethnicity is reported to be African American. This variant has been reported to ClinVar. It has been identified on the opposite chromosome from a pathogenic variant in unrelated individuals with OCA, type II. Two bioinformatic tools queried predict that this substitution (p.Ala368Val) would be damaging, and the alanine residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. Bioinformatic analysis predicts that this missense variant would not affect normal exon 10 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1103C>T to be likely pathogenic. - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
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 | Jan 30, 2024 | PM3_Strong, PP3, PM1 - |
not provided Pathogenic:3Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 368 of the OCA2 protein (p.Ala368Val). This variant is present in population databases (rs61745150, gnomAD 0.3%). This missense change has been observed in individual(s) with ocular albinism (PMID: 28451379; 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: 193574). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OCA2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Aug 18, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2023 | Reported previously in association with oculocutaneous albinism in published literature, either as a single heterozygous variant or phase unknown with a second variant (PMID: 26474496, 28451379, 32830442); 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: 10671067, 32830442, 23824587, 28451379, 26474496) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 16, 2018 | - - |
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2020 | The c.1103C>T (p.A368V) alteration is located in exon 10 (coding exon 9) of the OCA2 gene. This alteration results from a C to T substitution at nucleotide position 1103, causing the alanine (A) at amino acid position 368 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD) database, the OCA2 c.1103C>T alteration was observed in 0.03% (73/282508) of total alleles studied, with a frequency of 0.28% (70/24946) in the African subpopulation. This alteration was reported in a patient with oculocutaneous albinism presumably in trans with an exon 7 deletion (Gao, 2017) This amino acid position is well conserved in available vertebrate species. The p.A368V alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2023 | Variant summary: OCA2 c.1103C>T (p.Ala368Val) results in a non-conservative amino acid change located in the Citrate transporter-like domain (IPR004680) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251112 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.00022 vs 0.0043), allowing no conclusion about variant significance. c.1103C>T has been reported in the literature in individuals affected with Oculocutaneous Albinism (examples: Oetting_1998, Wolfson_2016, Gao_2017, Jackson_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28451379, 32830442, 10671067, 26474496). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) or pathogenic/likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
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