rs12910433

chr15-27983498-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000275.3(OCA2):c.1365-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,612,918 control chromosomes in the GnomAD database, including 345,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (23976 hom., cov: 32)
  • Exomes 𝑓: 0.64 (321523 hom.)
• Consequence: OCA2 NM_000275.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0380

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-27983498-G-A is Benign according to our data. Variant chr15-27983498-G-A is described in ClinVar as [Benign]. Clinvar id is 255720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-27983498-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCA2	NM_000275.3	c.1365-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000354638.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCA2	ENST00000354638.8	c.1365-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000275.3	P1
OCA2	ENST00000353809.9	c.1293-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76875 AN: 151970 Hom.: 23984 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.594

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.743

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.511

GnomAD3 exomes AF: 0.541 AC: 136088 AN: 251344 Hom.: 43003 AF XY: 0.547 AC XY: 74304 AN XY: 135850

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.356

Gnomad FIN exome AF: 0.742

Gnomad NFE exome AF: 0.714

Gnomad OTH exome AF: 0.594

GnomAD4 exome AF: 0.644 AC: 941109 AN: 1460830 Hom.: 321523 Cov.: 41 AF XY: 0.638 AC XY: 463606 AN XY: 726796

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.596

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.743

Gnomad4 NFE exome AF: 0.709

Gnomad4 OTH exome AF: 0.596

GnomAD4 genome AF: 0.505 AC: 76857 AN: 152088 Hom.: 23976 Cov.: 32 AF XY: 0.500 AC XY: 37181 AN XY: 74356

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.594

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.743

Gnomad4 NFE AF: 0.712

Gnomad4 OTH AF: 0.508

Alfa AF: 0.628 Hom.: 18008

Bravo AF: 0.472

Asia WGS AF: 0.296 AC: 1030 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Tyrosinase-positive oculocutaneous albinism Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.0
Dann	Benign	0.50

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: rs12910433; hg19: chr15-28228644; COSMIC: COSV62344987;