15-28022592-T-C

Variant names:

• chr15-28022592-T-C
• rs145242923
• NM_000275.3:c.574-19A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000275.3(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 NM_000275.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.304
• Publications: 5 publications found

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]

OCA2 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 504924.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00632 (962/152300) while in subpopulation NFE AF = 0.00919 (625/68024). AF 95% confidence interval is 0.00859. There are 7 homozygotes in GnomAd4. There are 446 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3	c.574-19A>G		intron_variant	Intron 5 of 23	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.574-19A>G		intron_variant	Intron 5 of 23	1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.574-19A>G		intron_variant	Intron 5 of 22	1		ENSP00000261276.8
OCA2	ENST00000431101.1	c.574-19A>G		intron_variant	Intron 5 of 6	3		ENSP00000415431.1
OCA2	ENST00000445578.5	c.573+2253A>G		intron_variant	Intron 5 of 5	3		ENSP00000414425.1

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

GnomAD2 exomes AF: 0.00652 AC: 1635 AN: 250850 AF XY: 0.00698

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 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

African (AFR) AF: 0.00154 AC: 51 AN: 33078

American (AMR) AF: 0.00680 AC: 304 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 283 AN: 25988

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39592

South Asian (SAS) AF: 0.00660 AC: 566 AN: 85786

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53280

Middle Eastern (MID) AF: 0.00768 AC: 44 AN: 5730

European-Non Finnish (NFE) AF: 0.0101 AC: 11089 AN: 1093434

Other (OTH) AF: 0.00789 AC: 471 AN: 59714

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

African (AFR) AF: 0.00236 AC: 98 AN: 41558

American (AMR) AF: 0.00876 AC: 134 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00768 AC: 37 AN: 4818

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00919 AC: 625 AN: 68024

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00806 Hom.: 15

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

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OCA2: BS1 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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% -

Tyrosinase-positive oculocutaneous albinism Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OCA2-related disorder Benign:1

Mar 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.13
DANN	Benign	0.35
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs145242923; hg19: chr15-28267738;