15-28081796-C-T

Position:

• chr15-28081796-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000275.3(OCA2):​c.79G>A​(p.Gly27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,612,778 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (4 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:4
• Conservation: PhyloP100: 0.128

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005886793).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00484 (738/152324) while in subpopulation AFR AF= 0.0162 (675/41578). AF 95% confidence interval is 0.0152. There are 9 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.79G>A	p.Gly27Arg	missense_variant	2/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.79G>A	p.Gly27Arg	missense_variant	2/24	1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.79G>A	p.Gly27Arg	missense_variant	2/23	1		ENSP00000261276
OCA2	ENST00000431101.1	c.79G>A	p.Gly27Arg	missense_variant	2/7	3		ENSP00000415431
OCA2	ENST00000445578.5	c.79G>A	p.Gly27Arg	missense_variant	2/6	3		ENSP00000414425

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 734 AN: 152206 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00137 AC: 332 AN: 242598 Hom.: 3 AF XY: 0.00111 AC XY: 147 AN XY: 132984

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000612

Gnomad ASJ exome AF: 0.00832

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000659 AC: 962 AN: 1460454 Hom.: 4 Cov.: 32 AF XY: 0.000567 AC XY: 412 AN XY: 726600

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00908

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00484 AC: 738 AN: 152324 Hom.: 9 Cov.: 33 AF XY: 0.00483 AC XY: 360 AN XY: 74490

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000966 Hom.: 0

Bravo AF: 0.00532

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00145 AC: 175

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2 Benign:2

Pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The OCA2 p.Gly27Arg variant was identified in 3 of 242 proband chromosomes (frequency: 0.037) from non-hispanic caucasian individuals with oculocutaneous albinism (OCA) (Hutton_2008_PMID:18463683). The variant was also identified in dbSNP (ID: rs61738394) and ClinVar (classified as pathogenic by EGL Genetics, likely pathogenic by Genetic Services Laboratory, University of Chicago and as a VUS by GeneDx). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 491 of 273964 chromosomes (3 homozygous) at a frequency of 0.001792 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 357 of 23176 chromosomes (freq: 0.0154), Ashkenazi Jewish in 85 of 10146 chromosomes (freq: 0.008378), Other in 9 of 7014 chromosomes (freq: 0.001283), Latino in 23 of 35144 chromosomes (freq: 0.000655), European (non-Finnish) in 14 of 123642 chromosomes (freq: 0.000113), East Asian in 1 of 19664 chromosomes (freq: 0.000051), European (Finnish) in 1 of 24704 chromosomes (freq: 0.00004) and South Asian in 1 of 30474 chromosomes (freq: 0.000033). In two Jewish families, two siblings with OCA2 were homozygous for the G27R variant and two siblings with OCA2 were compound heterozygous for the G27R and A481T variants, however the unaffected father was also compound heterozygous for G27R and A481T (Blumenfeld_2012). The p.Gly27 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2023	Observed with p.(L440F) on the same allele (in cis) in multiple unrelated individuals referred for genetic testing at GeneDx; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15173252, 23891399, 18463683, 15712365, 20981092, 23504663, 19626598, 18326704, 23824587, 9259203, 31636960, 27887888) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	OCA2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Tyrosinase-positive oculocutaneous albinism Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 08, 2023	Variant summary: OCA2 c.79G>A (p.Gly27Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 1612778 control chromosomes, predominantly at a frequency of 0.016 within the African or African-American subpopulation in the gnomAD database, including 13 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in OCA2 causing Oculocutaneous Albinism phenotype (0.0043), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.79G>A has been reported in the literature in individuals affected with Oculocutaneous Albinism without strong evidence for causality, as they were either not comprehensively genotyped, or harbored other putatively pathogenic variants in OCA2 and/or other Oculocutaneous Albinism-related genes (e.g. Spritz_1997, Oetting_2005, Hutton_2008a, Hutton_2008b). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Oculocutaneous Albinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18326704, 18463683, 15712365, 9259203). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Five submitters classified the variant as uncertain significance, two classified it as benign, and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 06, 2017	- -

OCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	6.0
DANN	Benign	0.81
DEOGEN2	Benign	0.28	.;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.61	T;T;.;.
MetaRNN	Benign	0.0059	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.90	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.54	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.80	T;T;T;T
Sift4G	Benign	0.66	T;T;.;T
Polyphen		0.0010	B;P;.;.
Vest4		0.59
MutPred		0.65		Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);
MVP		0.74
MPC		0.11
ClinPred		0.0023	T
GERP RS		-6.2
Varity_R		0.047
gMVP		0.19

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: rs61738394; hg19: chr15-28326942; COSMIC: COSV100667223;