rs41446944

Variant names:

• chr15-27966770-A-G
• rs41446944
• NM_000275.3:c.1556T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000275.3(OCA2):​c.1556T>C​(p.Val519Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,613,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.37
• Publications: 6 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: Uncertain_significance. The variant received 0 ACMG points.

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.1556T>C	p.Val519Ala	missense	Exon 15 of 24	NP_000266.2
	OCA2	NM_001300984.2		c.1484T>C	p.Val495Ala	missense	Exon 14 of 23	NP_001287913.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	ENST00000354638.8	TSL:1 MANE Select	c.1556T>C	p.Val519Ala	missense	Exon 15 of 24	ENSP00000346659.3
	OCA2	ENST00000353809.9	TSL:1	c.1484T>C	p.Val495Ala	missense	Exon 14 of 23	ENSP00000261276.8
	OCA2	ENST00000910120.1		c.1556T>C	p.Val519Ala	missense	Exon 15 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251386 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461364 Hom.: 0 Cov.: 32 AF XY: 0.000153 AC XY: 111 AN XY: 726992

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5396

European-Non Finnish (NFE) AF: 0.000189 AC: 210 AN: 1111958

Other (OTH) AF: 0.000265 AC: 16 AN: 60336

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74342

African (AFR) AF: 0.0000724 AC: 3 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.0000604

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.022
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.097	D
MutationAssessor	Benign	0.93	L
PhyloP100		8.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.68
Sift	Benign	0.18	T
Sift4G	Benign	0.15	T
Polyphen		0.078	B
Vest4		0.75
MVP		0.95
MPC		0.42
ClinPred		0.19	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.79
Mutation Taster		=7/93	disease causing

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: rs41446944; hg19: chr15-28211916;