rs141949212

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000275.3(OCA2):​c.2339G>A​(p.Gly780Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,612,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

OCA2
NM_000275.3 missense, splice_region

Scores

14
3
2
Splicing: ADA: 0.9997
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a topological_domain Extracellular (size 39) in uniprot entity P_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000275.3
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 15-27845052-C-T is Pathogenic according to our data. Variant chr15-27845052-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-27845052-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-27845052-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OCA2NM_000275.3 linkuse as main transcriptc.2339G>A p.Gly780Asp missense_variant, splice_region_variant 23/24 ENST00000354638.8 NP_000266.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OCA2ENST00000354638.8 linkuse as main transcriptc.2339G>A p.Gly780Asp missense_variant, splice_region_variant 23/241 NM_000275.3 ENSP00000346659 P1Q04671-1
OCA2ENST00000353809.9 linkuse as main transcriptc.2267G>A p.Gly756Asp missense_variant, splice_region_variant 22/231 ENSP00000261276 Q04671-2

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
151992
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000652
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251398
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.000554
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1460816
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726866
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
151992
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.000652
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000953
Hom.:
0
Bravo
AF:
0.000193
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Pathogenic:6
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 10, 2015- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratoire de Génétique Moléculaire, CHU Bordeaux-- -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022This missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). The variant is in trans with NM_000275.3:c.2360C>T. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000436090). A different missense change at the same codon (p.Gly780Ser) has been reported to be associated with OCA2-related disorder (PMID: 32741191). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 24, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJun 08, 2022PM2, PM3_Strong, PP3 -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 780 of the OCA2 protein (p.Gly780Asp). This variant is present in population databases (rs141949212, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of ocular albinism and/or oculocutaneous albinism (PMID: 28041643, 28976636, 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: 436090). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 25, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28041643, 28976636, 32581362, 31589614, 34838614, 29345414) -
Oculocutaneous albinism Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2023Variant summary: OCA2 c.2339G>A (p.Gly780Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251398 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (4e-05 vs 0.0043), allowing no conclusion about variant significance. c.2339G>A has been reported in the literature in multiple bi-allelic individuals affected with Oculocutaneous Albinism (example: Lasseaux_OCA2_PCMR_2018). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 29345414). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 04, 2024- -
OCA2-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 30, 2024The OCA2 c.2339G>A variant is predicted to result in the amino acid substitution p.Gly780Asp. This variant has been reported in individuals with oculocutaneous albinism (Table S2, patient G004719, Carss et al. 2017. PubMed ID: 28041643; Marti et al. 2018. PubMed ID: 28976636; Table S3, Lasseaux et al. 2018. PubMed ID: 29345414). Additionally, at PreventionGenetics, we have identified this variant, along with a second pathogenic OCA2 variant in at least six unrelated patients with oculocutaneous albinism. This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD, and has been classified as likely pathogenic and pathogenic by numerous labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/436090/). Given the evidence, we interpret c.2339G>A (p.Gly780Asp) as pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 03, 2018- -
Albinism Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 10, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
.;D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.018
T
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Pathogenic
4.1
.;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-6.2
D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.93
MVP
0.97
MPC
0.55
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.91
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs141949212; hg19: chr15-28090198; API