rs143218168

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP5BP4

The NM_000275.3(OCA2):c.1255C>T(p.Arg419Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R419Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

OCA2
NM_000275.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 0.581

Variant links:

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]

OCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 21) in uniprot entity P_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000275.3

PP5

Variant 15-27985173-G-A is Pathogenic according to our data. Variant chr15-27985173-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194160.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=3}. Variant chr15-27985173-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.07972804). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCA2	NM_000275.3 linkuse as main transcript	c.1255C>T	p.Arg419Trp	missense_variant	13/24	ENST00000354638.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCA2	ENST00000354638.8 linkuse as main transcript	c.1255C>T	p.Arg419Trp	missense_variant	13/24	1	NM_000275.3	P1	Q04671-1
OCA2	ENST00000353809.9 linkuse as main transcript	c.1183C>T	p.Arg395Trp	missense_variant	12/23	1			Q04671-2

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

246900

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

133832

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000242

AC:

353

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

171

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00227

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000218

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000512

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000939

Hom.:

Bravo

AF:

0.000710

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2023	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: 31229681, 9259203, 30025130, 30414346, 34426522, 31077556, 32552135, 34707637, 33124154, 34838614, 33808351, 37194472, 35488210) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 419 of the OCA2 protein (p.Arg419Trp). This variant is present in population databases (rs143218168, gnomAD 0.2%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 9259203, 21458243, 29345414, 31077556). 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: 194160). 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 expected to disrupt OCA2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Tyrosinase-positive oculocutaneous albinism

Pathogenic:1Uncertain:2

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, 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 Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous 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 arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (78 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12158 heterozygotes, 400 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated permease P domain (NCBI). (I) 0710 - Another missense variant has inconclusive previous evidence for pathogenicity. This alternative change at the same position (p.Arg419Gln) has been reported multiple times as benign and as a polymorphism, but has a weaker Grantham change (LOVD, ClinVar, PMID: 9259203). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as a VUS (ClinVar), but more recently described as pathogenic and observed in many compound heterozygous patients with oculocutaneous albinism (PMID: 9259203, PMID: 33124154; PMID: 23504663; PMID: 31229681; PMID: 29095814; PMID: 31077556). One patient also had occult macular dystrophy, but this is due to an additional variant in the RPL1L1 gene (PMID: 30025130). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 24, 2024

- -

OCA2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2024

The OCA2 c.1255C>T variant is predicted to result in the amino acid substitution p.Arg419Trp. This variant has been reported in individuals with autosomal recessive oculocutaneous albanism (OCA) (Spritz et al. 1997. PubMed ID: 9259203; Zobor et al. 2018. PubMed ID: 30025130; Zhong et al. 2019. PubMed ID: 31077556). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;D

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.76

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.080

T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Uncertain

2.8

.;M

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.58

MVP

0.97

MPC

0.49

ClinPred

0.21

GERP RS

0.60

Varity_R

0.40

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over