rs145242923

Positions:

• chr15-28022592-T-C
• chr15-28022592-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000354638.8(OCA2):​c.574-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,593,592 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (73 hom.)
• Consequence: OCA2 ENST00000354638.8 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.304

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 15-28022592-T-C is Benign according to our data. Variant chr15-28022592-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504924.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=3}.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.574-19A>G		intron_variant		ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.574-19A>G		intron_variant		1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.574-19A>G		intron_variant		1		ENSP00000261276
OCA2	ENST00000431101.1	c.574-19A>G		intron_variant		3		ENSP00000415431
OCA2	ENST00000445578.5	c.573+2253A>G		intron_variant		3		ENSP00000414425

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152182 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00747

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00652 AC: 1635 AN: 250850 Hom.: 10 AF XY: 0.00698 AC XY: 947 AN XY: 135666

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00645

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00849

Gnomad OTH exome AF: 0.00884

GnomAD4 exome AF: 0.00894 AC: 12882 AN: 1441292 Hom.: 73 Cov.: 28 AF XY: 0.00888 AC XY: 6377 AN XY: 718466

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.00680

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00660

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00789

GnomAD4 genome AF: 0.00632 AC: 962 AN: 152300 Hom.: 7 Cov.: 33 AF XY: 0.00599 AC XY: 446 AN XY: 74476

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00768

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00919

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00867 Hom.: 4

Bravo AF: 0.00642

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	OCA2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: outside ROI. OB 12/14/15: One compound het patient with with oc ular albinism who had exon 7 deletion and this variant was reported (Spritz 1995 ). Freq 1.1% -

OCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Tyrosinase-positive oculocutaneous albinism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.13
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs145242923; hg19: chr15-28267738;