rs1800407

chr15-27985172-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_000275.3(OCA2):c.1256G>A(p.Arg419Gln) variant causes a missense change. The variant allele was found at a frequency of 0.068 in 1,613,592 control chromosomes in the GnomAD database, including 4,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R419W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.049 (241 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4169 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 7.14

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 -16 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 21) in uniprot entity P_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000275.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-27985173-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194160.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=3}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0110088885).
• BP6: Variant 15-27985172-C-T is Benign according to our data. Variant chr15-27985172-C-T is described in ClinVar as [Benign]. Clinvar id is 963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-27985172-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCA2	NM_000275.3	c.1256G>A	p.Arg419Gln	missense_variant	13/24	ENST00000354638.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCA2	ENST00000354638.8	c.1256G>A	p.Arg419Gln	missense_variant	13/24	1	NM_000275.3	P1
OCA2	ENST00000353809.9	c.1184G>A	p.Arg395Gln	missense_variant	12/23	1

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7402 AN: 152172 Hom.: 241 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0429

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0709

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0469 AC: 11577 AN: 246792 Hom.: 345 AF XY: 0.0485 AC XY: 6492 AN XY: 133732

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0436

Gnomad ASJ exome AF: 0.0492

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0319

Gnomad FIN exome AF: 0.0441

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0559

GnomAD4 exome AF: 0.0700 AC: 102342 AN: 1461302 Hom.: 4169 Cov.: 35 AF XY: 0.0689 AC XY: 50090 AN XY: 726900

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.0457

Gnomad4 ASJ exome AF: 0.0496

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0313

Gnomad4 FIN exome AF: 0.0434

Gnomad4 NFE exome AF: 0.0803

Gnomad4 OTH exome AF: 0.0691

GnomAD4 genome AF: 0.0486 AC: 7403 AN: 152290 Hom.: 241 Cov.: 32 AF XY: 0.0474 AC XY: 3528 AN XY: 74452

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0670

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0315

Gnomad4 FIN AF: 0.0429

Gnomad4 NFE AF: 0.0710

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0676 Hom.: 887

Bravo AF: 0.0480

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0906 AC: 349

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.0778 AC: 669

ExAC AF: 0.0441 AC: 5353

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0730

EpiControl AF: 0.0708

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -
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

Mar 06, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

Affects, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	0.18	P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.57
Sift	Benign	0.094	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.99	D;D
Vest4		0.39
MPC		0.51
ClinPred		0.036	T
GERP RS		4.4
Varity_R		0.21
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800407; hg19: chr15-28230318; COSMIC: COSV62342487;