rs1800408

chr15-27985108-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM5 BP4_Moderate

The NM_000275.3(OCA2):c.1320G>C(p.Leu440Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L440S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:5 B:1
• Conservation: PhyloP100: 0.826

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 Uncertain_significance. Variant got 2 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, 9 uncertain in NM_000275.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-27985109-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 973316.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09535745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCA2	NM_000275.3	c.1320G>C	p.Leu440Phe	missense_variant	13/24	ENST00000354638.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCA2	ENST00000354638.8	c.1320G>C	p.Leu440Phe	missense_variant	13/24	1	NM_000275.3	P1
OCA2	ENST00000353809.9	c.1248G>C	p.Leu416Phe	missense_variant	12/23	1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000420 AC: 105 AN: 250002 Hom.: 0 AF XY: 0.000473 AC XY: 64 AN XY: 135268

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00837

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000888

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000239 AC: 350 AN: 1461722 Hom.: 0 Cov.: 34 AF XY: 0.000243 AC XY: 177 AN XY: 727142

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000719 Hom.: 1

Bravo AF: 0.000257

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2023	Identified in both the heterozygous and homozygous state in several individuals with oculocutaneous albinism in published literature, although some of these individuals also harbored additional variants (including G27R) in the OCA2 gene or in other genes that may also have contributed to their clinical phenotype; additional evidence to suggest pathogenicity or benign classification of the L440F variant was not provided in these studies (PMID: 7601462, 9259203, 18326704, 18463683); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12163334, 15889046, 17236130, 18463683, 9259203, 18326704, 23824587, 29345414, 18839200, 32830442, 23504663, 7601462) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 440 of the OCA2 protein (p.Leu440Phe). This variant is present in population databases (rs1800408, gnomAD 0.8%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 18326704, 18463683, 29345414; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 255719). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OCA2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Tyrosinase-positive oculocutaneous albinism Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 14, 2016	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 23, 2023

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2021

The c.1320G>C (p.L440F) alteration is located in exon 13 (coding exon 12) of the OCA2 gene. This alteration results from a G to C substitution at nucleotide position 1320, causing the leucine (L) at amino acid position 440 to be replaced by a phenylalanine (F). Based on data from gnomAD, the C allele has an overall frequency of 0.04% (109/281,394) total alleles studied. The highest observed frequency was 0.84% (87/10,322) of Ashkenazi Jewish alleles. This alteration was reported in two patients with oculocutaneous albinism type 2; one patient was homozygous for this alteration and the other was compound heterozygous with another missense alteration, c.1327G>A, (p.V443I) (Jackson, 2020). This variant has also been reported in additional patients with either limited clinical info (Simeonov, 2013; Lasseaux, 2018) or with multiple variants in this and other OCA genes (Hutton, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

OCA2-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 20, 2023

The OCA2 c.1320G>C variant is predicted to result in the amino acid substitution p.Leu440Phe. This variant has been reported in the homozygous and compound heterozygous states in individuals with oculocutaneous albinism (Table S3 in Lasseaux et al. 2018. PubMed ID: 29345414; Jackson et al. 2020. PubMed ID: 32830442). This variant has also been reported as a "third" variant in an individual who was homozygous for the OCA2 variant c.79G>A (p.Gly27Arg) (Hutton et al. 2008. PubMed ID: 18326704). This variant is reported in 0.84% of alleles in individuals of Ashkenazi Jewish descent and with a global allele frequency of 0.039% in gnomAD (http://gnomad.broadinstitute.org/variant/15-28230254-C-G), which is higher than expected for a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.095	T;T
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.11		.;Loss of stability (P = 0.0197);
MVP		0.99
MPC		0.50
ClinPred		0.14	T
GERP RS		-0.32
Varity_R		0.72
gMVP		0.94

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: rs1800408; hg19: chr15-28230254;