rs144812594

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000275.3(OCA2):c.1211C>T(p.Thr404Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000395 in 1,595,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T404T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

OCA2
NM_000275.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.54

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

oculocutaneous albinism type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, ClinGen

OCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

PP5

Variant 15-27986615-G-A is Pathogenic according to our data. Variant chr15-27986615-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 211766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3 link	c.1211C>T	p.Thr404Met	missense_variant	Exon 12 of 24	ENST00000354638.8	NP_000266.2	Q04671-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8 link	c.1211C>T	p.Thr404Met	missense_variant	Exon 12 of 24	1	NM_000275.3	ENSP00000346659.3		Q04671-1
OCA2	ENST00000353809.9 link	c.1139C>T	p.Thr380Met	missense_variant	Exon 11 of 23	1		ENSP00000261276.8		Q04671-2

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000636

AC:

AN:

251456

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1442890

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719260

show subpopulations

African (AFR)

AF:

0.000451

AC:

AN:

33234

American (AMR)

AF:

0.000112

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.00

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000822

AC:

AN:

1094510

Other (OTH)

AF:

0.0000167

AC:

AN:

59734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000210

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41548

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000904

Hom.:

Bravo

AF:

0.000208

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism

Pathogenic:4

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 22, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000211766). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 26, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2022

Centre for Human Genetics, University of Kinshasa

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces a conserved Threonine residue with a Methionine. This change is predicted damaging by the vast majority of prediction algorithms. This variant is very rare with no homozygous in gnomAD (AF: 0.0000636), was submitted to ClinVar by multiple submitters mostly classifying this variant as pathogenic/Likely pathogenic (VCV000211766.10), and is mentioned in at least three publications (PMID: 29345414‚ PMID: 10649493). Previous ClinVar submissions contain information regarding functional analysis demonstrating the pathogenic role of this variant. We identified this variant in a heterozygous state in one patient with Tyrosinase-positive oculocutaneous albinism in the Democratic Republic of Congo (DRC). This patient was heterozygous for the classic 2.7 deletion in the OCA2 gene. segregation analysis showed that the variant was in trans to the deletion in our patient. This variant was classified as pathogenic according to the ACMG guidelines -

not provided

Pathogenic:2

Mar 31, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 23824587, 33144682, 24361966, 28266639, 23504663, 27734839, 36116698, 7762554, 29345414, 34838614, 37334785, 37956964, 37471664, 19060277) -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 404 of the OCA2 protein (p.Thr404Met). This variant is present in population databases (rs144812594, gnomAD 0.07%). This missense change has been observed in individual(s) with ocular albinism (PMID: 23504663, 24361966, 27734839). 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: 211766). 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) 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. -

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

Pathogenic:1

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oculocutaneous albinism

Pathogenic:1

Aug 16, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: OCA2 c.1211C>T (p.Thr404Met) 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 6.4e-05 in 251456 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (6.4e-05 vs 0.0043), allowing no conclusion about variant significance. c.1211C>T has been reported in the literature in the presumed compound heterozygous state in multiple individuals affected with Oculocutaneous Albinism (example, Mauri_2017, Wei_2022, Simeonov_2013). These data indicate that the variant is likely to 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: 27734839, 24361966, 28266639, 23504663, 34838614). ClinVar contains an entry for this variant (Variation ID: 211766). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

OCA2-related disorder

Pathogenic:1

Feb 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The OCA2 c.1211C>T variant is predicted to result in the amino acid substitution p.Thr404Met. This variant has been reported in the compound heterozygous and homozygous states in individuals with oculocutaneous albinism (OCA) (Rimoldi et al. 2014. PubMed ID: 24361966; Shahzad et al. 2017. PubMed ID: 28266639). This variant has also been reported in a patient with OCA, but a second causative variant was not found (Grønskov et al. 2009. PubMed ID: 19060277, Table 3). At PreventionGenetics, this variant along with a second pathogenic variant has been found in several affected individuals. This variant is classified as likely pathogenic by several independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/211766/). Given the evidence, we classify c.1211C>T (p.Thr404Met) as pathogenic. -

Albinism or congenital nystagmus

Pathogenic:1

Jun 05, 2025

NHS Central & South Genomic Laboratory Hub

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES

Pathogenic:1

Mar 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nonsyndromic Oculocutaneous Albinism

Pathogenic:1

Mar 07, 2017

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

.;H

PhyloP100

8.5

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.93

MVP

1.0

MPC

0.49

ClinPred

0.94

GERP RS

5.6

Varity_R

0.77

gMVP

0.97

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over