NM_000275.3:c.1441G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A481V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 27 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 159 hom. )

Consequence

OCA2
NM_000275.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5B:8

Conservation

PhyloP100: 5.40

Publications

74 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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

OCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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.

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.1441G>A	p.Ala481Thr	missense	Exon 14 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.1369G>A	p.Ala457Thr	missense	Exon 13 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.1441G>A	p.Ala481Thr	missense	Exon 14 of 24	ENSP00000346659.3	Q04671-1
OCA2	ENST00000353809.9	TSL:1	c.1369G>A	p.Ala457Thr	missense	Exon 13 of 23	ENSP00000261276.8	Q04671-2
OCA2	ENST00000910120.1		c.1441G>A	p.Ala481Thr	missense	Exon 14 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

1018

AN:

152206

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00838

AC:

2108

AN:

251492

AF XY:

0.00792

show subpopulations

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 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.:

AF XY:

0.00464

AC XY:

3375

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.00268

AC:

120

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0177

AC:

463

AN:

26136

East Asian (EAS)

AF:

0.0527

AC:

2092

AN:

39700

South Asian (SAS)

AF:

0.000904

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0458

AC:

2445

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00122

AC:

1355

AN:

1111990

Other (OTH)

AF:

0.00508

AC:

307

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

419

839

1258

1678

2097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00668

AC:

1018

AN:

152324

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

672

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41578

American (AMR)

AF:

0.00275

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3472

East Asian (EAS)

AF:

0.0342

AC:

177

AN:

5182

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0545

AC:

578

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00194

AC:

132

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00377

Hom.:

Bravo

AF:

0.00258

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00775

AC:

941

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Tyrosinase-positive oculocutaneous albinism (9)

not provided (3)

not specified (2)

OCA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.014

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.8

PhyloP100

5.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.72

Sift

Benign

0.19

Sift4G

Benign

0.44

Polyphen

0.95

Vest4

0.89

MVP

0.92

MPC

0.46

ClinPred

0.068

GERP RS

5.1

Varity_R

0.27

gMVP

0.94

Mutation Taster

=26/74

polymorphism (auto)

(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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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

Computational scores

Splicing

Publications

Other links and lift over