15-28016172-CCAG-GACC

Position:

• chr15-28016172-CCAG-GACC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000354638.8(OCA2):​c.819_822delinsGGTC​(p.Asn273_Trp274delinsLysVal) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OCA2 ENST00000354638.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.59

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 15-28016172-CCAG-GACC is Pathogenic according to our data. Variant chr15-28016172-CCAG-GACC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.819_822delinsGGTC	p.Asn273_Trp274delinsLysVal	missense_variant	8/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.819_822delinsGGTC	p.Asn273_Trp274delinsLysVal	missense_variant	8/24	1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.819_822delinsGGTC	p.Asn273_Trp274delinsLysVal	missense_variant	8/23	1		ENSP00000261276
OCA2	ENST00000445578.5	c.585_588delinsGGTC	p.Asn195_Trp196delinsLysVal	missense_variant	6/6	3		ENSP00000414425

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Oct 24, 2023	This sequence variant is a four-nucleotide substitution (CTGG>GGTC) at positions 819-822 of the coding sequence of the OCA2 gene that results in an asparagine to lysine amino acid change at residue 273 and tryptophan to valine amino acid change at residue 274 of the OCA2 melanosomal transmembrane protein. These residues fall in the first lumil loop domain of the OCA2 protein (PMID: 25513726, UniProt). This is a previously reported variant (ClinVar 198707) that has been observed in individuals affected by oculocutaneous albinism (PMID: 18821858, 15173252, 12876664, 7874125, 37294081, 37707835, 28976636, 18680187). This variant is absent from the gnomAD population database (0/~251,000 alleles). The asparagine and tryptophan residues at this position are well conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 13, 2017	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 21, 2021	PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2024	In-frame deletion of 2 amino acids and insertion of 2 incorrect amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15173252, 18821858, 12876664, 7874125, 28976636, 18680187, 33502802, 37294081, Diallo2024[medRxiv]) -

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 22, 2024

- -

OCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2022

The OCA2 c.819_822delinsGGTC variant is predicted to result in an in-frame deletion and insertion. This variant has been reported to be causative for autosomal recessive oculocutaneous albinism (Garrison et al. 2004. PubMed ID: 15173252; King et al. 2003. PubMed ID: 12876664, reported as NW273KV; Lee. 1994. PubMed ID: 7874125, reported as N273K1W274V; Rooryck et al. 2008. PubMed ID: 18821858). At PreventionGenetics, we have observed this variant along with another pathogenic variant in several unrelated patients. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.819_822delinsGGTC (p.Asn273_Trp274delinsLysVal) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044784; hg19: chr15-28261318;