NM_000275.3:c.1183-4A>G

Variant names:

• chr15-27986647-T-C
• rs10852218
• NM_000275.3:c.1183-4A>G

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.1183-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,552,170 control chromosomes in the GnomAD database, including 500,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (41604 hom., cov: 32)
  • Exomes 𝑓: 0.80 (458828 hom.)
• Consequence: OCA2 NM_000275.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003896
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.153
• Publications: 22 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 15-27986647-T-C is Benign according to our data. Variant chr15-27986647-T-C is described in ClinVar as Benign. ClinVar VariationId is 193986.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.

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.1183-4A>G		splice_region intron	N/A	NP_000266.2
	OCA2	NM_001300984.2		c.1111-4A>G		splice_region intron	N/A	NP_001287913.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	ENST00000354638.8	TSL:1 MANE Select	c.1183-4A>G		splice_region intron	N/A	ENSP00000346659.3
	OCA2	ENST00000353809.9	TSL:1	c.1111-4A>G		splice_region intron	N/A	ENSP00000261276.8
	OCA2	ENST00000910120.1		c.1183-4A>G		splice_region intron	N/A	ENSP00000580179.1

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109567 AN: 152034 Hom.: 41603 Cov.: 32

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.873

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.872

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.832

Gnomad OTH AF: 0.735

GnomAD2 exomes AF: 0.782 AC: 196675 AN: 251390 AF XY: 0.780

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.726

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.836

Gnomad OTH exome AF: 0.796

GnomAD4 exome AF: 0.804 AC: 1126263 AN: 1400018 Hom.: 458828 Cov.: 27 AF XY: 0.800 AC XY: 560357 AN XY: 700506

African (AFR) AF: 0.453 AC: 14781 AN: 32624

American (AMR) AF: 0.724 AC: 32324 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 21130 AN: 25800

East Asian (EAS) AF: 0.999 AC: 39300 AN: 39350

South Asian (SAS) AF: 0.619 AC: 52678 AN: 85164

European-Finnish (FIN) AF: 0.870 AC: 46484 AN: 53404

Middle Eastern (MID) AF: 0.781 AC: 4422 AN: 5660

European-Non Finnish (NFE) AF: 0.824 AC: 869449 AN: 1055092

Other (OTH) AF: 0.784 AC: 45695 AN: 58282

GnomAD4 genome AF: 0.720 AC: 109600 AN: 152152 Hom.: 41604 Cov.: 32 AF XY: 0.721 AC XY: 53665 AN XY: 74398

African (AFR) AF: 0.472 AC: 19576 AN: 41484

American (AMR) AF: 0.700 AC: 10699 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 2823 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5178 AN: 5188

South Asian (SAS) AF: 0.616 AC: 2971 AN: 4820

European-Finnish (FIN) AF: 0.872 AC: 9238 AN: 10598

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.832 AC: 56543 AN: 67998

Other (OTH) AF: 0.732 AC: 1544 AN: 2108

Alfa AF: 0.781 Hom.: 24823

Bravo AF: 0.704

Asia WGS AF: 0.789 AC: 2742 AN: 3478

EpiCase AF: 0.820

EpiControl AF: 0.816

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Tyrosinase-positive oculocutaneous albinism (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.22
DANN	Benign	0.67
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.010
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: rs10852218; hg19: chr15-28231793;