15-27851392-A-G

Position:

• chr15-27851392-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000275.3(OCA2):​c.2328T>C​(p.Ala776=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,612,484 control chromosomes in the GnomAD database, including 152,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17884 hom., cov: 32)
  • Exomes 𝑓: 0.43 (134991 hom.)
• Consequence: OCA2 NM_000275.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.39

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-27851392-A-G is Benign according to our data. Variant chr15-27851392-A-G is described in ClinVar as [Benign]. Clinvar id is 195643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-27851392-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.2328T>C	p.Ala776=	synonymous_variant	22/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.2328T>C	p.Ala776=	synonymous_variant	22/24	1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.2256T>C	p.Ala752=	synonymous_variant	21/23	1		ENSP00000261276

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72097 AN: 151952 Hom.: 17866 Cov.: 32

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.533

GnomAD3 exomes AF: 0.435 AC: 107811 AN: 248098 Hom.: 24346 AF XY: 0.439 AC XY: 59018 AN XY: 134434

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.481

Gnomad EAS exome AF: 0.438

Gnomad SAS exome AF: 0.532

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.425 AC: 621378 AN: 1460416 Hom.: 134991 Cov.: 39 AF XY: 0.429 AC XY: 311663 AN XY: 726484

Gnomad4 AFR exome AF: 0.629

Gnomad4 AMR exome AF: 0.373

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.334

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.474 AC: 72148 AN: 152068 Hom.: 17884 Cov.: 32 AF XY: 0.471 AC XY: 35047 AN XY: 74332

Gnomad4 AFR AF: 0.617

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.419

Gnomad4 OTH AF: 0.536

Alfa AF: 0.447 Hom.: 9943

Bravo AF: 0.486

Asia WGS AF: 0.491 AC: 1708 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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)	Jan 21, 2015	- -
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 12, 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: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;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.2
DANN	Benign	0.55

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: rs1800419; hg19: chr15-28096538; COSMIC: COSV62337410;