rs797044784

Variant names:

• chr15-28016172-CCAG-GACC
• rs797044784
• NM_000275.3:c.819_822delCTGGinsGGTC

Variant summary

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

The NM_000275.3(OCA2):​c.819_822delCTGGinsGGTC​(p.AsnTrp273LysVal) 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 NM_000275.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 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 rank	MANE	Protein	UniProt
OCA2	NM_000275.3	c.819_822delCTGGinsGGTC	p.AsnTrp273LysVal	missense_variant		ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.819_822delCTGGinsGGTC	p.AsnTrp273LysVal	missense_variant		1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.819_822delCTGGinsGGTC	p.AsnTrp273LysVal	missense_variant		1		ENSP00000261276.8
OCA2	ENST00000445578.5	c.585_588delCTGGinsGGTC	p.AsnTrp195LysVal	missense_variant		3		ENSP00000414425.1

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:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Pathogenic:3

Nov 13, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Pathogenic:2 Uncertain:1

Mar 02, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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], 37707835) -

Dec 21, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

PM2 -

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

Feb 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OCA2-related disorder Pathogenic:1

Dec 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;