rs121918166

Variant names:

Your query was ambiguous. Multiple possible variants found:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received 11 ACMG points: 11P and 0B. PS3PM5PP3PP5_Strong

The NM_000275.3(OCA2):c.1327G>A (p.Val443Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00591 (AC=9,545) in the gnomAD database across 1,613,948 control chromosomes, including 39 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00749. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000390147: Functional studies demonstrated that the p.Val443Ile variant protein localized similarly to wild type but showed reduced activity of 85% and reduced pH regulation compared to wild-type (Bellono et al. 2014)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.V443A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1516182) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 36 hom. )

Consequence

OCA2
NM_000275.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:47U:1

Conservation

PhyloP100: 7.14

Publications

62 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet
oculocutaneous albinism
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

OCA2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000275.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

Well-established functional study supports damaging effect (PS3); SCV000390147: Functional studies demonstrated that the p.Val443Ile variant protein localized similarly to wild type but showed reduced activity of 85% and reduced pH regulation compared to wild-type (Bellono et al. 2014).; SCV000966900: "In vitro studies demonstrated that the p.Val443Ile variant results in a partial loss of protein function (Sviderskaya 1997, Bellono 2014)."; SCV001142446: Functional studies demonstrate that the V443I variant disrupts ion conductance, which is required for melanin production (PMID: 27231233).; SCV002572351: The most pronounced variant effect results in near abolishment of normal ion channel activity as measured by OCA2-mediated chloride current measurements in-vitro. Bellono_2014; SCV004177044: Functional studies show the variant reduced protein function and altered protein localization (Bellono NW et al., PMID: 25513726; Sviderskaya EV et al., PMID: 8980282).; SCV005397365: Studies examining the functiol consequence of this variant demonstrate impaired protein function leading to reduced/absent melanin production (PMID: 8980282, 25513726).; SCV005416988: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.; SCV000329644: Published functional studies demonstrate that this variant disrupts ion conductance, which is required for melanin production (Bellono et al., 2014); SCV001553011: A functional study expressing the OCA2 mutant cDNA containing p.Val443Ile in mouse melanocytes showed decreased melanin production compared to wildtype (Sviderskaya_1997_PMID: 8980282). Another functional study also demonstrated that the p.Val443Ile variant protein localized similarly to wild-type but showed reduced activity of 85% and reduced pH regulation compared to wild-type (Bellano_2014_PMID: 25513726).; SCV001586228: Experimental studies have shown that this missense change affects OCA2 function (PMID: 8980282, 25513726).; SCV000742020: Functional analysis demonstrated that transfection of the p.V433I mutant protein into immortalized melanocytes that are null for OCA2 was unable to correct for deficient melanin biosynthesis and hypopigmentation compared to cells transfected with wild-type protein (Sviderskaya, 1997). Additionally, Bellono (2014) showed that OCA2 mediates chloride-selective anion conductance and although mutant V443I localization remains intact, it had significantly reduced amplitudes compared to wild-type OCA2.

PM5

Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.V443A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 1516182)

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	NM_000275.3	MANE Select	c.1327G>A	p.Val443Ile	missense	Exon 13 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.1255G>A	p.Val419Ile	missense	Exon 12 of 23	NP_001287913.1	Q04671-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OCA2	ENST00000354638.8	TSL:1 MANE Select	c.1327G>A	p.Val443Ile	missense	Exon 13 of 24	ENSP00000346659.3	Q04671-1
OCA2	ENST00000353809.9	TSL:1	c.1255G>A	p.Val419Ile	missense	Exon 12 of 23	ENSP00000261276.8	Q04671-2
OCA2	ENST00000910120.1		c.1327G>A	p.Val443Ile	missense	Exon 13 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

513

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00607

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00305

AC:

762

AN:

250050

AF XY:

0.00296

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00369

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.000789

Gnomad NFE exome

AF:

0.00513

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00618

AC:

9032

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00592

AC XY:

4307

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

33472

American (AMR)

AF:

0.00208

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

26130

East Asian (EAS)

AF:

0.000277

AC:

AN:

39698

South Asian (SAS)

AF:

0.000128

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000712

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00762

AC:

8477

AN:

1111924

Other (OTH)

AF:

0.00424

AC:

256

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

481

963

1444

1926

2407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<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:

0.00337

AC:

513

AN:

152262

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

229

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41568

American (AMR)

AF:

0.000719

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.000581

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00607

AC:

413

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00516

Hom.:

Bravo

AF:

0.00351

Asia WGS

AF:

0.000577

AC:

AN:

3478

Local populations

Turkish Variome

AF:

0.000647

AC:

AN:

1546

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000781

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.00342

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tyrosinase-positive oculocutaneous albinism (25)

not provided (14)

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (2)

Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (2)

Albinism or congenital nystagmus (1)

Autosomal recessive OCA2-related disorders (1)

Inborn genetic diseases (1)

OCA2-related disorder (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.045

MetaRNN

Benign

0.036

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.7

PhyloP100

7.1

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.99

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Varity_R

0.46

gMVP

0.90

Mutation Taster

=73/27

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over