rs1800413

Positions:

• chr15-27957597-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate

The NM_000275.3(OCA2):​c.1775C>T​(p.Thr592Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.26

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 8 ACMG points.

• PS1: Transcript NM_000275.3 (OCA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a topological_domain Cytoplasmic (size 89) in uniprot entity P_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_000275.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.1775C>T	p.Thr592Ile	missense_variant	16/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.1775C>T	p.Thr592Ile	missense_variant	16/24	1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.1703C>T	p.Thr568Ile	missense_variant	15/23	1		ENSP00000261276.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;D
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.10	B;P
Vest4		0.72
MutPred		0.85		.;Loss of disorder (P = 0.0806);
MVP		0.98
MPC		0.47
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.40
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1800413; hg19: chr15-28202743;