rs34731820

Variant names:

• chr15-27990583-A-G
• rs34731820
• NM_000275.3:c.1109T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000275.3(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 NM_000275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 6.22

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• 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: {Likely_benign=1, Benign=1, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00335 (510/152324) while in subpopulation AFR AF= 0.0119 (494/41580). AF 95% confidence interval is 0.011. There are 4 homozygotes in gnomad4. There are 232 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3	c.1109T>C	p.Ile370Thr	missense_variant	Exon 10 of 24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.1109T>C	p.Ile370Thr	missense_variant	Exon 10 of 24	1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.1045-917T>C		intron_variant	Intron 9 of 22	1		ENSP00000261276.8

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 508 AN: 152206 Hom.: 4 Cov.: 32

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.: 0 AF XY: 0.000604 AC XY: 82 AN XY: 135756

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.: 5 Cov.: 30 AF XY: 0.000301 AC XY: 219 AN XY: 727152

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.: 4 Cov.: 32 AF XY: 0.00311 AC XY: 232 AN XY: 74492

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.: 0

Bravo AF: 0.00373

ExAC AF: 0.000997 AC: 121

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 26, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tyrosinase-positive oculocutaneous albinism Uncertain:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 20, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OCA2-related disorder Benign:1

Aug 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0060	B
Vest4		0.85
MVP		0.96
MPC		0.14
ClinPred		0.042	T
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

Other links and lift over

dbSNP: rs34731820; hg19: chr15-28235729;