rs34731820

Positions:

chr15-27990583-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The ENST00000354638.8(OCA2):c.1109T>C(p.Ile370Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000613 in 1,614,014 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 5 hom. )

Consequence

OCA2
ENST00000354638.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 6.22

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 -7 ACMG points.

PM1

In a transmembrane_region Helical (size 16) in uniprot entity P_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in ENST00000354638.8

BP4

Computational evidence support a benign effect (MetaRNN=0.01856479).

BP6

Variant 15-27990583-A-G is Benign according to our data. Variant chr15-27990583-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419971.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=3}.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3 linkuse as main transcript	c.1109T>C	p.Ile370Thr	missense_variant	10/24	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.1109T>C	p.Ile370Thr	missense_variant	10/24	1	NM_000275.3	ENSP00000346659	P1	Q04671-1
OCA2	ENST00000353809.9 linkuse as main transcript	c.1045-917T>C		intron_variant		1		ENSP00000261276		Q04671-2

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

508

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000868

AC:

218

AN:

251172

Hom.:

AF XY:

0.000604

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000328

AC:

480

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

219

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.0125

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.00335

AC:

510

AN:

152324

Hom.:

Cov.:

AF XY:

0.00311

AC XY:

232

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000604

Hom.:

Bravo

AF:

0.00373

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 12, 2017	The OCA2 c.1109T>C (p.Ile370Thr) missense variant has been reported in one study in which it was found in a compound heterozygous state with a second missense variant in one individual with an unusual hypopigmentation type, and in a heterozygous state in another individual with a skin color resembling that of rufus oculocutaneous albinism, in whom a second variant was not detected (Kerr et al. 2000). The Ile370 residue is conserved. Control data are unavailable for this variant, which is reported at a frequency of 0.025253 in the Esan in Nigeria population of the 1000 Genomes Project. Based on the evidence, the p.Ile370Thr variant is classified as a variant of uncertain significance but suspicious for pathogenicity for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2017	The I370T variant in the OCA2 gene has been reported previously in two unrelated individuals of African descent with an unusual hypopigmentation phenotype suggestive of oculocutaneous albinism (OCA). The I370T variant was reported along with a second variant in an individual with light brown eyes and yellow-ish white colored hair. The second individual was heterozygous for the I370T variant, with no second variant identified, and had reddish-brown colored skin (Kerr et al., 2000). The I370T variant is observed in 114/10360 (1.1%) alleles from individuals of African background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The I370T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I370T as a variant of uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 20, 2015

- -

OCA2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.65

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.088

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

MetaRNN

Benign

0.019

MetaSVM

Uncertain

-0.081

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.86

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.52

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0060

Polyphen

0.0060

Vest4

0.85

MVP

0.96

MPC

0.14

ClinPred

0.042

GERP RS

4.8

Varity_R

0.27

gMVP

0.84

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

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