rs1800407

Positions:

chr15-27985172-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The NM_000275.3(OCA2):c.1256G>A(p.Arg419Gln) variant causes a missense change. The variant allele was found at a frequency of 0.068 in 1,613,592 control chromosomes in the GnomAD database, including 4,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R419W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.049 ( 241 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4169 hom. )

Consequence

OCA2
NM_000275.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 7.14

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 Benign. Variant got -16 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 21) in uniprot entity P_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000275.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-27985173-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0110088885).

BP6

Variant 15-27985172-C-T is Benign according to our data. Variant chr15-27985172-C-T is described in ClinVar as [Benign]. Clinvar id is 963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-27985172-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3 linkuse as main transcript	c.1256G>A	p.Arg419Gln	missense_variant	13/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8 linkuse as main transcript	c.1256G>A	p.Arg419Gln	missense_variant	13/24	1	NM_000275.3	ENSP00000346659	P1	Q04671-1
OCA2	ENST00000353809.9 linkuse as main transcript	c.1184G>A	p.Arg395Gln	missense_variant	12/23	1		ENSP00000261276		Q04671-2

Frequencies

GnomAD3 genomes

AF:

0.0486

AC:

7402

AN:

152172

Hom.:

241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.0671

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.0429

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0709

Gnomad OTH

AF:

0.0512

GnomAD3 exomes

AF:

0.0469

AC:

11577

AN:

246792

Hom.:

345

AF XY:

0.0485

AC XY:

6492

AN XY:

133732

show subpopulations

Gnomad AFR exome

AF:

0.0114

Gnomad AMR exome

AF:

0.0436

Gnomad ASJ exome

AF:

0.0492

Gnomad EAS exome

AF:

0.000327

Gnomad SAS exome

AF:

0.0319

Gnomad FIN exome

AF:

0.0441

Gnomad NFE exome

AF:

0.0648

Gnomad OTH exome

AF:

0.0559

GnomAD4 exome

AF:

0.0700

AC:

102342

AN:

1461302

Hom.:

4169

Cov.:

AF XY:

0.0689

AC XY:

50090

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.0110

Gnomad4 AMR exome

AF:

0.0457

Gnomad4 ASJ exome

AF:

0.0496

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.0313

Gnomad4 FIN exome

AF:

0.0434

Gnomad4 NFE exome

AF:

0.0803

Gnomad4 OTH exome

AF:

0.0691

GnomAD4 genome

AF:

0.0486

AC:

7403

AN:

152290

Hom.:

241

Cov.:

AF XY:

0.0474

AC XY:

3528

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0141

Gnomad4 AMR

AF:

0.0670

Gnomad4 ASJ

AF:

0.0493

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0315

Gnomad4 FIN

AF:

0.0429

Gnomad4 NFE

AF:

0.0710

Gnomad4 OTH

AF:

0.0502

Alfa

AF:

0.0676

Hom.:

887

Bravo

AF:

0.0480

TwinsUK

AF:

0.0863

AC:

320

ALSPAC

AF:

0.0906

AC:

349

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0778

AC:

669

ExAC

AF:

0.0441

AC:

5353

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0730

EpiControl

AF:

0.0708

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Tyrosinase-positive oculocutaneous albinism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Other:1

Affects, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

.;D

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.5

.;L

MutationTaster

Benign

0.18

P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.57

Sift

Benign

0.094

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.99

D;D

Vest4

0.39

MPC

0.51

ClinPred

0.036

GERP RS

4.4

Varity_R

0.21

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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