15-28018408-G-A

Position:

chr15-28018408-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000275.3(OCA2):c.796C>T(p.Arg266Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,613,918 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 32 hom. )

Consequence

OCA2
NM_000275.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.620

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:

OCA2 (HGNC:):

OCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064091086).

BP6

Variant 15-28018408-G-A is Benign according to our data. Variant chr15-28018408-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-28018408-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00861 (1311/152284) while in subpopulation AFR AF= 0.0258 (1072/41554). AF 95% confidence interval is 0.0245. There are 23 homozygotes in gnomad4. There are 635 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3 linkuse as main transcript	c.796C>T	p.Arg266Trp	missense_variant	7/24	ENST00000354638.8	NP_000266.2	Q04671-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OCA2	ENST00000354638.8 linkuse as main transcript	c.796C>T	p.Arg266Trp	missense_variant	7/24	1	NM_000275.3	ENSP00000346659.3	Q04671-1
OCA2	ENST00000353809.9 linkuse as main transcript	c.796C>T	p.Arg266Trp	missense_variant	7/23	1		ENSP00000261276.8	Q04671-2
OCA2	ENST00000445578.5 linkuse as main transcript	c.574-2222C>T		intron_variant		3		ENSP00000414425.1	C9JLG9
OCA2	ENST00000431101.1 linkuse as main transcript	c.*4C>T		downstream_gene_variant		3		ENSP00000415431.1	C9JDV3

Frequencies

GnomAD3 genomes

AF:

0.00860

AC:

1308

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00184

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00460

AC:

1153

AN:

250492

Hom.:

AF XY:

0.00468

AC XY:

635

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0131

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00308

AC:

4508

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

2411

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0252

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00440

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0122

Gnomad4 FIN exome

AF:

0.000263

Gnomad4 NFE exome

AF:

0.00190

Gnomad4 OTH exome

AF:

0.00431

GnomAD4 genome

AF:

0.00861

AC:

1311

AN:

152284

Hom.:

Cov.:

AF XY:

0.00853

AC XY:

635

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0258

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00184

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00285

Hom.:

Bravo

AF:

0.00914

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.0245

AC:

108

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00522

AC:

634

Asia WGS

AF:

0.0270

AC:

AN:

3476

EpiCase

AF:

0.00164

EpiControl

AF:

0.00207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	OCA2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Tyrosinase-positive oculocutaneous albinism

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

.;D

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.85

T;D

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;D

Vest4

0.30

MVP

0.81

MPC

0.10

ClinPred

0.037

GERP RS

0.0067

Varity_R

0.12

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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