15-27851481-G-C

Variant names:

• chr15-27851481-G-C
• rs368772032
• NM_000275.3:c.2245-6C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000275.3(OCA2):​c.2245-6C>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 0.00000343 in 1,459,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OCA2 NM_000275.3 splice_region, intron
• Scores: Splicing: ADA: 0.003915
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.42
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-27851481-G-C is Pathogenic according to our data. Variant chr15-27851481-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436091.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45). . Strength limited to SUPPORTING due to the PP5.

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.2245-6C>G		splice_region intron	N/A	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.2173-6C>G		splice_region intron	N/A	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.2245-6C>G		splice_region intron	N/A	ENSP00000346659.3	Q04671-1
	OCA2	ENST00000353809.9	TSL:1	c.2173-6C>G		splice_region intron	N/A	ENSP00000261276.8	Q04671-2
	OCA2	ENST00000910120.1		c.2491-6C>G		splice_region intron	N/A	ENSP00000580179.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000205 AC: 5 AN: 243536 AF XY: 0.0000303

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000277

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459232 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725740

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 85634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110698

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Tyrosinase-positive oculocutaneous albinism (1)
1	-	-	Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: -6

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

Other links and lift over

dbSNP: rs368772032; hg19: chr15-28096627;