Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 12P and 3B. PM1PM5PP5_Very_StrongBP4BS1_SupportingBS2_Supporting

The ENST00000354638.8(OCA2):c.1327G>A(p.Val443Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00591 in 1,613,948 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V443A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 36 hom. )

Consequence

OCA2
ENST00000354638.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:39U: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: 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in ENST00000354638.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-27985100-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1516182.

PP5

Variant 15-27985101-C-T is Pathogenic according to our data. Variant chr15-27985101-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.035922796). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00618 (9032/1461686) while in subpopulation NFE AF = 0.00762 (8477/1111924). AF 95% confidence interval is 0.00749. There are 36 homozygotes in GnomAdExome4. There are 4307 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000354638.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	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
	OCA2	NM_001300984.2		c.1255G>A	p.Val419Ile	missense	Exon 12 of 23	NP_001287913.1

Ensembl Transcripts

Selected	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
	OCA2	ENST00000353809.9	TSL:1	c.1255G>A	p.Val419Ile	missense	Exon 12 of 23	ENSP00000261276.8

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

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00281

AC:

341

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tyrosinase-positive oculocutaneous albinism (20)

not provided (13)

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

Albinism or congenital nystagmus (1)

Inborn genetic diseases (1)

OCA2-related disorder (1)

See cases (1)

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

Polyphen

1.0

Vest4

0.82

MVP

0.91

MPC

0.44

ClinPred

0.11

GERP RS

5.2

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

Publications

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rs28934272

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over