15-27951878-G-A

Variant names:

• chr15-27951878-G-A
• rs7164127
• NM_000275.3:c.1857C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000275.3(OCA2):​c.1857C>T​(p.Asp619Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.000552 in 1,611,848 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: OCA2 NM_000275.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 5.28
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 15-27951878-G-A is Benign according to our data. Variant chr15-27951878-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 888345.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	NM_000275.3	MANE Select	c.1857C>T	p.Asp619Asp	synonymous	Exon 18 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.1785C>T	p.Asp595Asp	synonymous	Exon 17 of 23	NP_001287913.1	Q04671-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	ENST00000354638.8	TSL:1 MANE Select	c.1857C>T	p.Asp619Asp	synonymous	Exon 18 of 24	ENSP00000346659.3	Q04671-1
	OCA2	ENST00000353809.9	TSL:1	c.1785C>T	p.Asp595Asp	synonymous	Exon 17 of 23	ENSP00000261276.8	Q04671-2
	OCA2	ENST00000910120.1		c.1857C>T	p.Asp619Asp	synonymous	Exon 18 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000462 AC: 116 AN: 251298 AF XY: 0.000456

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000541 AC: 789 AN: 1459542 Hom.: 0 Cov.: 30 AF XY: 0.000554 AC XY: 402 AN XY: 726242

African (AFR) AF: 0.000778 AC: 26 AN: 33422

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86186

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000640 AC: 710 AN: 1109908

Other (OTH) AF: 0.000298 AC: 18 AN: 60304

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74460

African (AFR) AF: 0.00118 AC: 49 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000732 Hom.: 0

Bravo AF: 0.000627

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Tyrosinase-positive oculocutaneous albinism (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	OCA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.5
DANN	Benign	0.34
PhyloP100		5.3
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7164127; hg19: chr15-28197024; COSMIC: COSV62356073;