rs1800417

Positions:

• chr15-27871233-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000275.3(OCA2):​c.2165T>C​(p.Ile722Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00381 in 1,614,112 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (57 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (61 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.15

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 -18 ACMG points.

• PM1: In a transmembrane_region Helical (size 16) in uniprot entity P_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000275.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.006563753).
• BP6: Variant 15-27871233-A-G is Benign according to our data. Variant chr15-27871233-A-G is described in ClinVar as [Benign]. Clinvar id is 255728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCA2	NM_000275.3	c.2165T>C	p.Ile722Thr	missense_variant	21/24	ENST00000354638.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCA2	ENST00000354638.8	c.2165T>C	p.Ile722Thr	missense_variant	21/24	1	NM_000275.3	P1
OCA2	ENST00000353809.9	c.2093T>C	p.Ile698Thr	missense_variant	20/23	1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2368 AN: 152190 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00497 AC: 1247 AN: 251092 Hom.: 23 AF XY: 0.00385 AC XY: 523 AN XY: 135730

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000952

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00257 AC: 3754 AN: 1461804 Hom.: 61 Cov.: 32 AF XY: 0.00233 AC XY: 1698 AN XY: 727208

Gnomad4 AFR exome AF: 0.0538

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000790

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.0157 AC: 2395 AN: 152308 Hom.: 57 Cov.: 33 AF XY: 0.0149 AC XY: 1107 AN XY: 74480

Gnomad4 AFR AF: 0.0505

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00458 Hom.: 17

Bravo AF: 0.0186

ESP6500AA AF: 0.0540 AC: 238

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00579 AC: 703

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Tyrosinase-positive oculocutaneous albinism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.7
DANN	Benign	0.31
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0066	T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.28
Sift	Benign	0.37	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0	B;B
Vest4		0.32
MVP		0.67
MPC		0.11
ClinPred		0.0026	T
GERP RS		3.6
Varity_R		0.021
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800417; hg19: chr15-28116379; COSMIC: COSV62344637;