rs117315845

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001292063.2(OTOG):c.8369G>A(p.Arg2790His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,550,166 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2790C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 10 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.72

Publications

6 publications found

Variant links:

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]

OTOG Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062504113).

BP6

Variant 11-17642200-G-A is Benign according to our data. Variant chr11-17642200-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226920.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00204 (311/152296) while in subpopulation AMR AF = 0.00288 (44/15298). AF 95% confidence interval is 0.00222. There are 1 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.8369G>A	p.Arg2790His	missense_variant	Exon 53 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.8405G>A	p.Arg2802His	missense_variant	Exon 52 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.8369G>A	p.Arg2790His	missense_variant	Exon 53 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.8405G>A	p.Arg2802His	missense_variant	Exon 52 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

311

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00261

AC:

384

AN:

147302

AF XY:

0.00271

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.0000928

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00289

Gnomad OTH exome

AF:

0.00422

GnomAD4 exome

AF:

0.00233

AC:

3258

AN:

1397870

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1587

AN XY:

689454

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

31590

American (AMR)

AF:

0.00289

AC:

103

AN:

35678

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

296

AN:

25166

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35734

South Asian (SAS)

AF:

0.00251

AC:

199

AN:

79188

European-Finnish (FIN)

AF:

0.0000208

AC:

AN:

48118

Middle Eastern (MID)

AF:

0.00791

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00224

AC:

2413

AN:

1078728

Other (OTH)

AF:

0.00314

AC:

182

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

171

341

512

682

853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00204

AC:

311

AN:

152296

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41568

American (AMR)

AF:

0.00288

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00253

AC:

172

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00251

Hom.:

Bravo

AF:

0.00232

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.00281

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOG: BP4

Meniere disease

Uncertain:1

Jan 01, 2020

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:case-control

not specified

Benign:1

Sep 08, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg2802His in exon 52 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (54/14664) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 117315845).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.070

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

2.7

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.79

N;.

REVEL

Benign

0.059

Sift

Benign

0.23

T;.

Sift4G

Uncertain

0.032

D;D

Vest4

0.12

ClinPred

0.017

GERP RS

1.8

Varity_R

0.038

gMVP

0.32

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over