NM_000275.3:c.1503+5G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000275.3(OCA2):​c.1503+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000427 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

OCA2
NM_000275.3 splice_region, intron

Scores

2
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.19
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 Likely_pathogenic. Variant got 8 ACMG points.

PP5
Variant 15-27983340-C-T is Pathogenic according to our data. Variant chr15-27983340-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-27983340-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OCA2NM_000275.3 linkc.1503+5G>A splice_region_variant, intron_variant Intron 14 of 23 ENST00000354638.8 NP_000266.2 Q04671-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OCA2ENST00000354638.8 linkc.1503+5G>A splice_region_variant, intron_variant Intron 14 of 23 1 NM_000275.3 ENSP00000346659.3 Q04671-1
OCA2ENST00000353809.9 linkc.1431+5G>A splice_region_variant, intron_variant Intron 13 of 22 1 ENSP00000261276.8 Q04671-2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152144
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251490
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000397
AC:
58
AN:
1461844
Hom.:
0
Cov.:
32
AF XY:
0.0000330
AC XY:
24
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
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:
0.0000468
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152262
Hom.:
0
Cov.:
33
AF XY:
0.0000806
AC XY:
6
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000831

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Pathogenic:3
May 31, 2016
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 26, 2015
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:2
Dec 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 14 of the OCA2 gene. It does not directly change the encoded amino acid sequence of the OCA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs368124046, gnomAD 0.01%). This variant has been observed in individuals with oculocutaneous albinism (PMID: 24361966, 29345414; internal data). ClinVar contains an entry for this variant (Variation ID: 211768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24361966). For these reasons, this variant has been classified as Pathogenic. -

Jul 13, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Published functional studies demonstrate the use of a cryptic splice donor site within intron 14, with sequencing of aberrant transcript demonstrating it results in a frameshift, starting with codon Glycine 502, changing this amino acid to a Valine residue, and creating a premature Stop codon at position 84 of the new reading frame, denoted p.Gly502ValfsX84 (Rimoldi et al., 2014).; This variant is associated with the following publications: (PMID: 15712365, 10649493, 24361966, 31077556) -

SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Mar 25, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

OCA2-related disorder Pathogenic:1
Sep 04, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The OCA2 c.1503+5G>A variant is predicted to interfere with splicing. This intronic variant is predicted to weaken the nearby splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). A functional study using RT-PCR analysis confirmed that this variant results in an abnormal mRNA transcript due to splicing errors (Rimoldi et al. 2014. PubMed ID: 24361966). This variant has been reported in multiple individuals with oculocutaneous albinism (Rimoldi et al. 2014. PubMed ID: 24361966; Zhong et al. 2019. PubMed ID: 31077556). Given the evidence, we interpret this variant as pathogenic. -

Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
Apr 22, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.15
CADD
Benign
16
DANN
Benign
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.76
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.76
Position offset: 5

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: rs368124046; hg19: chr15-28228486; COSMIC: COSV62358743; API