rs61745150

chr15-27990589-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:3 O:1
• 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]

ACMG classification

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: {Pathogenic=3, Likely_pathogenic=6, not_provided=1, Uncertain_significance=3}. 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: 117 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251112 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135720

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1461662 Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 37 AN XY: 727134

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74478

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.00109

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 30, 2024	PM3_Strong, PP3, PM1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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	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 Pathogenic:3 Uncertain:2

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2014	- -
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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 16, 2018	- -
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) -

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 31, 2023

- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.055	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.88	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.64
MVP		0.99
MPC		0.45
ClinPred		0.12	T
GERP RS		5.9
Varity_R		0.65
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61745150; hg19: chr15-28235735;