15-27966612-A-G

Variant names:

• chr15-27966612-A-G
• rs4778218
• NM_000275.3:c.1636+78T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000275.3(OCA2):​c.1636+78T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 1,543,398 control chromosomes in the GnomAD database, including 536,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57516 hom., cov: 32)
  • Exomes 𝑓: 0.83 (478825 hom.)
• Consequence: OCA2 NM_000275.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.433
• Publications: 14 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-27966612-A-G is Benign according to our data. Variant chr15-27966612-A-G is described in ClinVar as Benign. ClinVar VariationId is 1224918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3	c.1636+78T>C		intron_variant	Intron 15 of 23	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.1636+78T>C		intron_variant	Intron 15 of 23	1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.1564+78T>C		intron_variant	Intron 14 of 22	1		ENSP00000261276.8

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131580 AN: 152082 Hom.: 57464 Cov.: 32

Gnomad AFR AF: 0.966

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.752

Gnomad ASJ AF: 0.822

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.836

Gnomad OTH AF: 0.833

GnomAD4 exome AF: 0.827 AC: 1150872 AN: 1391198 Hom.: 478825 AF XY: 0.821 AC XY: 571824 AN XY: 696146

African (AFR) AF: 0.970 AC: 31168 AN: 32130

American (AMR) AF: 0.754 AC: 33532 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 21164 AN: 25596

East Asian (EAS) AF: 0.998 AC: 39152 AN: 39228

South Asian (SAS) AF: 0.665 AC: 55990 AN: 84226

European-Finnish (FIN) AF: 0.872 AC: 46054 AN: 52840

Middle Eastern (MID) AF: 0.818 AC: 3648 AN: 4458

European-Non Finnish (NFE) AF: 0.830 AC: 872372 AN: 1050424

Other (OTH) AF: 0.826 AC: 47792 AN: 57848

GnomAD4 genome AF: 0.865 AC: 131688 AN: 152200 Hom.: 57516 Cov.: 32 AF XY: 0.861 AC XY: 64055 AN XY: 74396

African (AFR) AF: 0.966 AC: 40129 AN: 41548

American (AMR) AF: 0.751 AC: 11468 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 2850 AN: 3468

East Asian (EAS) AF: 0.998 AC: 5144 AN: 5156

South Asian (SAS) AF: 0.668 AC: 3214 AN: 4814

European-Finnish (FIN) AF: 0.872 AC: 9252 AN: 10614

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.836 AC: 56827 AN: 68008

Other (OTH) AF: 0.835 AC: 1766 AN: 2114

Alfa AF: 0.843 Hom.: 150530

Bravo AF: 0.867

Asia WGS AF: 0.843 AC: 2929 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.66
DANN	Benign	0.70
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4778218; hg19: chr15-28211758;