chr15-28022554-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

The NM_000275.3(OCA2):c.593C>T(p.Pro198Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,770 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).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

OCA2
NM_000275.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:2

Conservation

PhyloP100: 7.71

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 15-28022554-G-A is Pathogenic according to our data. Variant chr15-28022554-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198063.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=4, Likely_pathogenic=3}. Variant chr15-28022554-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.09873241). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 24	ENST00000354638.8	NP_000266.2	Q04671-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OCA2	ENST00000354638.8 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 24	1	NM_000275.3	ENSP00000346659.3	Q04671-1
OCA2	ENST00000353809.9 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 23	1		ENSP00000261276.8	Q04671-2
OCA2	ENST00000431101.1 link	c.593C>T	p.Pro198Leu	missense_variant	Exon 6 of 7	3		ENSP00000415431.1	C9JDV3
OCA2	ENST00000445578.5 link	c.573+2291C>T		intron_variant	Intron 5 of 5	3		ENSP00000414425.1	C9JLG9

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251266

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.000925

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000341

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000208

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Mar 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 32552135, 22995991, 12713581, 30609409, 25919014, 19865097, 18821858, 24118800, 31196117, 34838614) -

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the OCA2 protein (p.Pro198Leu). This variant is present in population databases (rs183487020, gnomAD 0.1%). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 19865097, 25919014, 29437493; internal data). ClinVar contains an entry for this variant (Variation ID: 198063). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt OCA2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Tyrosinase-positive oculocutaneous albinism

Pathogenic:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion, Medical Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OCA2 related disorder (ClinVar ID: VCV000198063, PMID:12713581, PS1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88, PP3_P). A missense variant is a common mechanism associated with Albinism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000124, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 27, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro198Leu (NM_000275.2 c.593C>T) variant in OCA2 has been reported in at l east 1 homozygous, 2 compound heterozygous and 1 heterozygous individuals of Tur kish, Chinese and Japanese ancestry with oculocutaneous albinism II (Rooryck 200 8, Suzuki 2003, Wang 2015, and Wei 2010). This variant has also been reported in ClinVar (Variation ID# 198063). This variant has been identified in 0.12% (13/1 0222) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs183487020). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a r ecessive carrier frequency. Computational prediction tools and conservation anal ysis suggest that the p.Pro198Leu variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, altho ugh additional studies are required to fully establish its clinical significance , the p.Pro198Leu variant is likely pathogenic based upon its biallelic observat ions in multiple affected individuals and low population frequency. -

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

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES

Pathogenic:1

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

.;D;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;.

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.5

M;M;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.75

MVP

0.99

MPC

0.41

ClinPred

0.17

GERP RS

3.8

Varity_R

0.31

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over