rs74653330

Positions:

• chr15-27983407-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BA1

The NM_000275.3(OCA2):​c.1441G>A​(p.Ala481Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00489 in 1,614,194 control chromosomes in the GnomAD database, including 186 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 0.0067 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (159 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:8
• Conservation: PhyloP100: 5.40

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 Benign. Variant got -10 ACMG points.

• PM1: In a topological_domain Extracellular (size 72) in uniprot entity P_HUMAN there are 19 pathogenic changes around while only 1 benign (95%) in NM_000275.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.014360964).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.1441G>A	p.Ala481Thr	missense_variant	14/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.1441G>A	p.Ala481Thr	missense_variant	14/24	1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.1369G>A	p.Ala457Thr	missense_variant	13/23	1		ENSP00000261276

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 1018 AN: 152206 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00838 AC: 2108 AN: 251492 Hom.: 53 AF XY: 0.00792 AC XY: 1077 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.0246

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.0477

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00471 AC: 6880 AN: 1461870 Hom.: 159 Cov.: 32 AF XY: 0.00464 AC XY: 3375 AN XY: 727240

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0527

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.0458

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00668 AC: 1018 AN: 152324 Hom.: 27 Cov.: 32 AF XY: 0.00902 AC XY: 672 AN XY: 74474

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00366 Hom.: 17

Bravo AF: 0.00258

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00775 AC: 941

Asia WGS AF: 0.0260 AC: 89 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Pathogenic:2 Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous albinism and oculocutaneous, type II albinism (MIM#203200). (I) 0106 - This gene is associated with autosomal recessive disease. A single variant has been reported in two families with dominant oculocutaneous albinism (PMID: 32741191). (I) 0115 - Variants in this gene causing oculocutaneous albininism are known to have variable expressivity (PMID: 24518832). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0307 - Variant is present in gnomAD (v3) at a frequency >=0.05 in the European subpopulation (964 heterozygotes, 27 homozygotes). (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated transmembrane helix within the permease P domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as pathogenic and a VUS, but more recently as likely benign and benign (ClinVar, LOVD). The variant has been described as a polymorphism that may lower pigmentation in healthy individuals (PMID: 25809079, PMID: 31196117), but also as a pathogenic or hypomorphic allele (PMID: 31719542, PMID: 32741191). (I) 1010 - Functional evidence for this variant is inconclusive. Transfected cells demonstrated a reduction to 70% of wildtype enzyme activity (ClinVar, PMID: 8980282). (I) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Cys777Tyr)). (I) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 12, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Institute for Genomic Medicine, Nationwide Children's Hospital	Apr 20, 2021	The p.Ala481Thr variant in OCA2 was identified by research genome sequencing and shown to segregate with disease in a Pakistani kindred with autosomal recessive ocular albinism (PMID: 34476810). The variant is predicted to cause a missense change (p.Ala481Thr) that is damaging according to many in silico tools including REVEL (0.72). It has been reported in OCA2 patients of Chinese (PMID: 34707637), European (PMID: 8302318) or Japanese (PMID: 31141302) ancestry, either in homozygous form or compound-heterozygous with another variant. The phenotype of patients harboring p.Ala481Thr variants is often described as less severe and its pathogenicity is much debated in the literature. The widely-cited functional impact for this variant (70% of wild-type activity) derives from a single experiment reported more than two decades ago. In 1997, Sviderskaya et al performed complementation studies of melanocytes and melanoblasts from OCA2-null mice in which transfection of mutant p.Ala481Thr cDNAs results in only partial melanin biosynthesis and hypopigmentation compared to transfection with wildtype cDNAs (PMID: 8980282). Many studies arguing against the pathogenicity of this variant originate from a research team in Japan, where the population prevalence of p.Ala481Thr is the highest (MAF ~0.051 in gnoMADv4) and it has been seen in homozygous form in both OCA2 patients and normally-pigmented homozygous carriers (PMIDs 12687678, 12713581). Population studies in East Asia have demonstrated that the derived allele is primarily restricted to northern East Asia (PMID: PMIDs: 17568986, 27081560). It is also common among North European Finnish individuals (MAF ~0.47 in gnoMADv4). This geographic distribution combined with the genetic association of p.Ala481Thr with skin pigmentation (PMID 25809079) is consistent with convergent evolution in East Asia and Europe ((PMIDs: 17182896, 17233754, 22065085). The latest release of the gnomAD database (v4) includes many more individuals from South Asia in which the p.Ala481Thr variant is very rare (MAF~0.0009). This supports the notion that population ancestry and selection history should be considered when interpreting the prevalence of this variant and its apparent phenotype. We consider the variant likely pathogenic. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	Does not cause OCA2 by itself, even when present in the homozygous state, but may result in a mild form of OCA2 when present in trans with a null or nearly null allele (Suzuki et al., 2003; Kawai et al., 2005; Wei et al., 2013); Observed more frequently in individuals with lighter iris and skin pigmentation than in controls in cohort studies (Abe et al., 2013; Eaton et al., 2015; Andersen et al., 2016); Published functional studies demonstrate that this variant retains approximately 70% of wildtype protein function (Sviderskaya et al., 1997); Reported as a common benign variant in individuals of East Asian background, and individuals homozygous for A481T were reported to have normal pigmentation for their ethnicity (Yuasa et al., 2007); This variant is associated with the following publications: (PMID: 23324268, 15942220, 20981092, 8302318, 12727022, 10905897, 17008060, 25333069, 30414346, 31077556, 34426522, 31719542, 25809079, 32901917, 23165166, 24617981, 17568986, 8980282, 12687678, 27468418) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	OCA2: BS1, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	Variant summary: OCA2 c.1441G>A (p.Ala481Thr) results in a non-conservative amino acid change located in the Citrate transporter-like domain (IPR004680) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0084 in 251492 control chromosomes in the gnomAD database, including 53 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in OCA2 causing Oculocutaneous Albinism phenotype (0.0043), strongly suggesting that the variant is benign. c.1441G>A has been reported as a common variant in East Asians and individuals with this variant may be less resistant to the stress of sunburn (Yuasa_2007). At least one publication reports experimental evidence evaluating an impact on protein function and reported the variant retained approximately 70-75% of wild-type protein function (Sviderskaya_1997). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4), benign/likely benign (n=5)and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 patient with ocular albinism in trans with a splice variant (Lee 1994), 1 Japanese patient with subclinical albinisim who was refered to clinic for severe sunburns (Kawai 2008), 3 Japanese patients with mild disease who has second variants in OCA2 (not clear whether they tested they are in cis or trans) (Suzuki 2003). Transfection of mouse melanocytes with human OCA2 Ala481Thr cDNA resulted in 70% functional activity (Sviderskaya 1997; full text not available). Variant has 4.7% frequency in European population and 20 homozygotes reported in ExAC. ClinVar classification is based on OMIM. Based on the frequency and the studies reporting this variant, it is likely to be a benign variant and lead to a subclinical phenotype at most, therefore does not meet criteria for reporting in BabySeq. -

OCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 21, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.19	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.95	P;B
Vest4		0.89
MVP		0.92
MPC		0.46
ClinPred		0.068	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs74653330; hg19: chr15-28228553; COSMIC: COSV62361319;