rs121918166

Variant names:

• chr15-27985101-C-T
• rs121918166
• NM_000275.3:c.1327G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-27985101-C-T
• chr15-27985101-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 12P and 3B. PM1 PM5 PP5_Very_Strong BP4 BS1_Supporting BS2_Supporting

The NM_000275.3(OCA2):​c.1327G>A​(p.Val443Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00591 in 1,613,948 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V443A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (36 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:39 U:1
• Conservation: PhyloP100: 7.14
• Publications: 62 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_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000275.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-27985100-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1516182.
• PP5: Variant 15-27985101-C-T is Pathogenic according to our data. Variant chr15-27985101-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.035922796). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00618 (9032/1461686) while in subpopulation NFE AF = 0.00762 (8477/1111924). AF 95% confidence interval is 0.00749. There are 36 homozygotes in GnomAdExome4. There are 4307 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1327G>A	p.Val443Ile	missense	Exon 13 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.1255G>A	p.Val419Ile	missense	Exon 12 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.1327G>A	p.Val443Ile	missense	Exon 13 of 24	ENSP00000346659.3	Q04671-1
	OCA2	ENST00000353809.9	TSL:1	c.1255G>A	p.Val419Ile	missense	Exon 12 of 23	ENSP00000261276.8	Q04671-2
	OCA2	ENST00000910120.1		c.1327G>A	p.Val443Ile	missense	Exon 13 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152144 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00305 AC: 762 AN: 250050 AF XY: 0.00296

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00369

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00618 AC: 9032 AN: 1461686 Hom.: 36 Cov.: 34 AF XY: 0.00592 AC XY: 4307 AN XY: 727128

African (AFR) AF: 0.00143 AC: 48 AN: 33472

American (AMR) AF: 0.00208 AC: 93 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26130

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86248

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00762 AC: 8477 AN: 1111924

Other (OTH) AF: 0.00424 AC: 256 AN: 60382

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152262 Hom.: 3 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74440

African (AFR) AF: 0.00132 AC: 55 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00607 AC: 413 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00516 Hom.: 16

Bravo AF: 0.00351

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
19	1	-	Tyrosinase-positive oculocutaneous albinism (20)
13	-	-	not provided (13)
2	-	-	Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (2)
1	-	-	Albinism or congenital nystagmus (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	OCA2-related disorder (1)
1	-	-	See cases (1)
1	-	-	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.036	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.91
MPC		0.44
ClinPred		0.11	T
GERP RS		5.2
Varity_R		0.46
gMVP		0.90
Mutation Taster		=73/27	disease causing (ClinVar)

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: rs121918166; hg19: chr15-28230247; COSMIC: COSV62340961;