rs33929465

Variant names:

• chr15-28018408-G-A
• rs33929465
• NM_000275.3:c.796C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-28018408-G-A
• chr15-28018408-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000275.3(OCA2):​c.796C>T​(p.Arg266Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,613,918 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0086 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (32 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.620
• Publications: 14 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

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, 6 uncertain in NM_000275.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0064091086).
• BP6: Variant 15-28018408-G-A is Benign according to our data. Variant chr15-28018408-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00861 (1311/152284) while in subpopulation AFR AF = 0.0258 (1072/41554). AF 95% confidence interval is 0.0245. There are 23 homozygotes in GnomAd4. There are 635 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

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.796C>T	p.Arg266Trp	missense	Exon 7 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.796C>T	p.Arg266Trp	missense	Exon 7 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.796C>T	p.Arg266Trp	missense	Exon 7 of 24	ENSP00000346659.3	Q04671-1
	OCA2	ENST00000353809.9	TSL:1	c.796C>T	p.Arg266Trp	missense	Exon 7 of 23	ENSP00000261276.8	Q04671-2
	OCA2	ENST00000910120.1		c.796C>T	p.Arg266Trp	missense	Exon 7 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes AF: 0.00860 AC: 1308 AN: 152170 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00460 AC: 1153 AN: 250492 AF XY: 0.00468

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00308 AC: 4508 AN: 1461634 Hom.: 32 Cov.: 32 AF XY: 0.00332 AC XY: 2411 AN XY: 727146

African (AFR) AF: 0.0252 AC: 845 AN: 33472

American (AMR) AF: 0.00172 AC: 77 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0122 AC: 1055 AN: 86256

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53288

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.00190 AC: 2114 AN: 1111904

Other (OTH) AF: 0.00431 AC: 260 AN: 60390

GnomAD4 genome AF: 0.00861 AC: 1311 AN: 152284 Hom.: 23 Cov.: 33 AF XY: 0.00853 AC XY: 635 AN XY: 74458

African (AFR) AF: 0.0258 AC: 1072 AN: 41554

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00410 Hom.: 13

Bravo AF: 0.00914

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00522 AC: 634

Asia WGS AF: 0.0270 AC: 93 AN: 3476

EpiCase AF: 0.00164

EpiControl AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	Tyrosinase-positive oculocutaneous albinism (1)
-	-	1	Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.62
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.30
MVP		0.81
MPC		0.10
ClinPred		0.037	T
GERP RS		0.0067
Varity_R		0.12
gMVP		0.54
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs33929465; hg19: chr15-28263554; COSMIC: COSV62347932; COSMIC: COSV62347932;