rs121918171
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000275.3(OCA2):c.1182G>A(p.Met394Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
OCA2
NM_000275.3 missense, splice_region
NM_000275.3 missense, splice_region
Scores
11
5
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.96
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 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, 7 uncertain in NM_000275.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-27989601-C-T is Pathogenic according to our data. Variant chr15-27989601-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 965.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OCA2 | NM_000275.3 | c.1182G>A | p.Met394Ile | missense_variant, splice_region_variant | 11/24 | ENST00000354638.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.1182G>A | p.Met394Ile | missense_variant, splice_region_variant | 11/24 | 1 | NM_000275.3 | P1 | |
OCA2 | ENST00000353809.9 | c.1110G>A | p.Met370Ile | missense_variant, splice_region_variant | 10/23 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135820
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461576Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727080
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GnomAD4 genome ? Cov.: 32
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?
Cov.:
32
ExAC
?
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1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2005 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
0.89
.;Gain of catalytic residue at L397 (P = 0.5066);
MVP
MPC
0.51
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -42
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at