chr15-28018482-G-C

Variant names:

• chr15-28018482-G-C
• rs2305253
• NM_000275.3:c.722C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000275.3(OCA2):​c.722C>G​(p.Pro241Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,613,584 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P241L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (49 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.998
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029698312).
• BP6: Variant 15-28018482-G-C is Benign according to our data. Variant chr15-28018482-G-C is described in ClinVar as Benign. ClinVar VariationId is 284034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0528 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.722C>G	p.Pro241Arg	missense	Exon 7 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.722C>G	p.Pro241Arg	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.722C>G	p.Pro241Arg	missense	Exon 7 of 24	ENSP00000346659.3	Q04671-1
	OCA2	ENST00000353809.9	TSL:1	c.722C>G	p.Pro241Arg	missense	Exon 7 of 23	ENSP00000261276.8	Q04671-2
	OCA2	ENST00000910120.1		c.722C>G	p.Pro241Arg	missense	Exon 7 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152178 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0583

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00460 AC: 1145 AN: 248756 AF XY: 0.00419

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00339

Gnomad EAS exome AF: 0.0596

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00131 AC: 1914 AN: 1461292 Hom.: 49 Cov.: 32 AF XY: 0.00128 AC XY: 929 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.000112 AC: 5 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26128

East Asian (EAS) AF: 0.0420 AC: 1669 AN: 39692

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53120

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111860

Other (OTH) AF: 0.00169 AC: 102 AN: 60332

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152292 Hom.: 5 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.0582 AC: 302 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000483 Hom.: 0

Bravo AF: 0.00224

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00404 AC: 490

Asia WGS AF: 0.0110 AC: 38 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	OCA2-related disorder (1)
-	-	1	Tyrosinase-positive oculocutaneous albinism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.15
Sift	Benign	0.19	T
Sift4G	Benign	0.25	T
Polyphen		0.75	P
Vest4		0.22
MVP		0.68
MPC		0.22
ClinPred		0.054	T
GERP RS		1.4
Varity_R		0.041
gMVP		0.39
Mutation Taster		=97/3	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: rs2305253; hg19: chr15-28263628; COSMIC: COSV107418624;