rs757286784

Positions:

• chr15-27986643-T-A
• chr15-27986643-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000354638.8(OCA2):​c.1183A>T​(p.Met395Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000141 in 1,422,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M395T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OCA2 ENST00000354638.8 missense, splice_region
• Scores: Splicing: ADA: 0.2124
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.16

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000354638.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 15-27986643-T-A is Pathogenic according to our data. Variant chr15-27986643-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1469112.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.1183A>T	p.Met395Leu	missense_variant, splice_region_variant	12/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.1183A>T	p.Met395Leu	missense_variant, splice_region_variant	12/24	1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.1111A>T	p.Met371Leu	missense_variant, splice_region_variant	11/23	1		ENSP00000261276

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1422658 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 710596

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000339

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1469112). This missense change has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 7874125; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 395 of the OCA2 protein (p.Met395Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.79	.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.8	.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.85		.;Gain of catalytic residue at M395 (P = 0.2731);
MVP		0.97
MPC		0.41
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.21
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.020		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: chr15-28231789;