rs74653330

Variant names:

• chr15-27983407-C-A
• NM_000275.3:c.1441G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-27983407-C-A
• chr15-27983407-C-G
• chr15-27983407-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000275.3(OCA2):​c.1441G>T​(p.Ala481Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A481T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.40

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Extracellular (size 72) in uniprot entity P_HUMAN there are 19 pathogenic changes around while only 1 benign (95%) in NM_000275.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-27983407-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3	c.1441G>T	p.Ala481Ser	missense_variant	Exon 14 of 24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.1441G>T	p.Ala481Ser	missense_variant	Exon 14 of 24	1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.1369G>T	p.Ala457Ser	missense_variant	Exon 13 of 23	1		ENSP00000261276.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.27	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.86	P;B
Vest4		0.59
MutPred		0.78		.;Gain of glycosylation at A481 (P = 0.0171);
MVP		0.86
MPC		0.39
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.29
gMVP		0.91

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-28228553;