rs1800417

Variant names:

• chr15-27871233-A-G
• rs1800417
• NM_000275.3:c.2165T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:5
• Conservation: PhyloP100: 5.15
• Publications: 9 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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000275.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	NM_000275.3	MANE Select	c.2165T>C	p.Ile722Thr	missense	Exon 21 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.2093T>C	p.Ile698Thr	missense	Exon 20 of 23	NP_001287913.1	Q04671-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	ENST00000354638.8	TSL:1 MANE Select	c.2165T>C	p.Ile722Thr	missense	Exon 21 of 24	ENSP00000346659.3	Q04671-1
	OCA2	ENST00000353809.9	TSL:1	c.2093T>C	p.Ile698Thr	missense	Exon 20 of 23	ENSP00000261276.8	Q04671-2
	OCA2	ENST00000910120.1		c.2369T>C	p.Ile790Thr	missense	Exon 22 of 26	ENSP00000580179.1

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

GnomAD2 exomes AF: 0.00497 AC: 1247 AN: 251092 AF XY: 0.00385

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 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

African (AFR) AF: 0.0538 AC: 1801 AN: 33464

American (AMR) AF: 0.00456 AC: 204 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 436 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.000790 AC: 878 AN: 1111962

Other (OTH) AF: 0.00634 AC: 383 AN: 60392

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

African (AFR) AF: 0.0505 AC: 2099 AN: 41570

American (AMR) AF: 0.00719 AC: 110 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68014

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00684 Hom.: 42

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Tyrosinase-positive oculocutaneous albinism (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.68	N
PhyloP100		5.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.28
Sift	Benign	0.37	T
Sift4G	Benign	0.66	T
Polyphen		0.0	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
Mutation Taster		=100/0	polymorphism (auto)

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