chr15-27990589-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4
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
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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000769 AC: 117AN: 152200Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251112Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135720
GnomAD4 exome AF: 0.0000657 AC: 96AN: 1461662Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 37AN XY: 727134
GnomAD4 genome AF: 0.000768 AC: 117AN: 152318Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56AN XY: 74478
ClinVar
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:4Other:1
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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. -
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. -
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PM3_Strong, PP3, PM1 -
not provided Pathogenic:3Uncertain:2
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; internal data). 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). 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) has been performed 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. -
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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, 37882226, 37650133, 38219857) -
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SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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 gnomAD, the T allele has an overall frequency of 0.026% (73/282508) total alleles studied. The highest observed frequency was 0.281% (70/24946) of African alleles. This variant has been identified in the homozygous state and/or in conjunction with other OCA2 variants in individuals with features consistent with OCA2-related oculocutaneous albinism; in at least one instance, the variants were identified in trans (Ambry internal data; Gao, 2017; Michaud, 2023). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
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not specified Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at