15-28022626-G-C

Variant names:

• chr15-28022626-G-C
• rs41276938
• NM_000275.3:c.574-53C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BS1_Supporting BS2_Supporting

The NM_000275.3(OCA2):​c.574-53C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,354,468 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (78 hom.)
• Consequence: OCA2 NM_000275.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00602 (917/152296) while in subpopulation NFE AF = 0.00992 (675/68030). AF 95% confidence interval is 0.0093. There are 2 homozygotes in GnomAd4. There are 407 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3	c.574-53C>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.574-53C>G		intron_variant	Intron 5 of 23	1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.574-53C>G		intron_variant	Intron 5 of 22	1		ENSP00000261276.8
OCA2	ENST00000431101.1	c.574-53C>G		intron_variant	Intron 5 of 6	3		ENSP00000415431.1
OCA2	ENST00000445578.5	c.573+2219C>G		intron_variant	Intron 5 of 5	3		ENSP00000414425.1

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 917 AN: 152178 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.00719

GnomAD4 exome AF: 0.00857 AC: 10297 AN: 1202172 Hom.: 78 AF XY: 0.00828 AC XY: 5056 AN XY: 610814

African (AFR) AF: 0.00256 AC: 73 AN: 28484

American (AMR) AF: 0.00674 AC: 297 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.00811 AC: 198 AN: 24406

East Asian (EAS) AF: 0.00 AC: 0 AN: 38538

South Asian (SAS) AF: 0.00113 AC: 91 AN: 80592

European-Finnish (FIN) AF: 0.000766 AC: 40 AN: 52190

Middle Eastern (MID) AF: 0.0112 AC: 59 AN: 5286

European-Non Finnish (NFE) AF: 0.0104 AC: 9136 AN: 876600

Other (OTH) AF: 0.00775 AC: 403 AN: 52030

GnomAD4 genome AF: 0.00602 AC: 917 AN: 152296 Hom.: 2 Cov.: 33 AF XY: 0.00546 AC XY: 407 AN XY: 74480

African (AFR) AF: 0.00274 AC: 114 AN: 41560

American (AMR) AF: 0.00412 AC: 63 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00992 AC: 675 AN: 68030

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00635

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Uncertain:1

Apr 19, 2024

MVZ Medizinische Genetik Mainz

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.53
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs41276938; hg19: chr15-28267772;