rs797044784

chr15-28016172-CCAG-GACC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PP5

The NM_000275.3(OCA2):c.819_822delinsGGTC(p.Asn273_Trp274delinsLysVal) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 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 Uncertain_significance. Variant got 2 ACMG points.

• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198707.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, Uncertain_significance=1}.

Transcripts

RefSeq

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

Ensembl

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

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	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	Jul 23, 2023	In-frame deletion of 2 amino acids and insertion of 2 incorrect amino acids; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15173252, 18821858, 12876664, 7874125, 28976636, 18680187, 33502802) -

Tyrosinase-positive oculocutaneous albinism Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 19, 2023

- -

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;