11-17561709-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001292063.2(OTOG):c.1546C>T(p.Arg516Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,550,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
OTOG
NM_001292063.2 missense
NM_001292063.2 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 3.54
Genes affected
OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOG | NM_001292063.2 | c.1546C>T | p.Arg516Cys | missense_variant | 15/56 | ENST00000399397.6 | |
OTOG | NM_001277269.2 | c.1582C>T | p.Arg528Cys | missense_variant | 14/55 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOG | ENST00000399397.6 | c.1546C>T | p.Arg516Cys | missense_variant | 15/56 | 5 | NM_001292063.2 | P2 | |
OTOG | ENST00000399391.7 | c.1582C>T | p.Arg528Cys | missense_variant | 14/55 | 5 | A2 | ||
OTOG | ENST00000498332.5 | n.1452C>T | non_coding_transcript_exon_variant | 14/16 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152066Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000155 AC: 23AN: 148498Hom.: 0 AF XY: 0.000212 AC XY: 17AN XY: 80032
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GnomAD4 exome AF: 0.000129 AC: 180AN: 1398284Hom.: 0 Cov.: 31 AF XY: 0.000142 AC XY: 98AN XY: 689664
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 09, 2018 | The p.Arg528Cys variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 12/22594 South Asian chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbS NP rs755375116). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analyses suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the p.Arg528Cys variant is unce rtain. ACMG/AMP Criteria applied: PP3. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 528 of the OTOG protein (p.Arg528Cys). This variant is present in population databases (rs755375116, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 506267). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Vest4
MutPred
Loss of catalytic residue at R528 (P = 0.0604);.;
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at