rs61734214

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001292063.2(OTOG):c.2512G>C(p.Gly838Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,550,570 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0083 ( 22 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 13 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:5

Conservation

PhyloP100: 7.38

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065345466).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00834 (1270/152278) while in subpopulation AFR AF = 0.0297 (1234/41536). AF 95% confidence interval is 0.0283. There are 22 homozygotes in GnomAd4. There are 589 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.2512G>C	p.Gly838Arg	missense_variant	Exon 21 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.2548G>C	p.Gly850Arg	missense_variant	Exon 20 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.2512G>C	p.Gly838Arg	missense_variant	Exon 21 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.2548G>C	p.Gly850Arg	missense_variant	Exon 20 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes

AF:

0.00831

AC:

1265

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

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:

0.00624

GnomAD2 exomes

AF:

0.00158

AC:

236

AN:

149554

AF XY:

0.00127

show subpopulations

Gnomad AFR exome

AF:

0.0306

Gnomad AMR exome

AF:

0.000936

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000850

AC:

1189

AN:

1398292

Hom.:

Cov.:

AF XY:

0.000761

AC XY:

525

AN XY:

689670

show subpopulations

African (AFR)

AF:

0.0321

AC:

1014

AN:

31596

American (AMR)

AF:

0.000896

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48216

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

1078908

Other (OTH)

AF:

0.00184

AC:

107

AN:

58016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00834

AC:

1270

AN:

152278

Hom.:

Cov.:

AF XY:

0.00791

AC XY:

589

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0297

AC:

1234

AN:

41536

American (AMR)

AF:

0.00137

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00618

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00266

Hom.:

Bravo

AF:

0.00934

ExAC

AF:

0.00187

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meniere disease

Pathogenic:1

Feb 03, 2025

Meniere Disease Neuroscience Research Program, Faculty of Medicine and Health, Kolling Institute, The University of Sydney

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The NM_001292063.2:c.2512G>C is a rare missense variant in the OTOG gene that was found in a Brazilian patient with Menière's Disease carrying two more rare missense variants in the same gene (M_001292063.2:c.3683C>T and NM_001292063.2:c.3350C>T). This variant has an amino acid change at p.G838R (p.G850R). In silico analysis using pathogenicity prediction algorithms such as the CADD score (27.6), and PolyPhen2 score (1.000), as well as ACMG guidelines for variant interpretation (PS4, PM2, PP3, PP2, BP1), have deemed the variant as "Likely Pathogenic. In silico Protein stability predictions such as DynaMut2 (-0.44kcal/mol) and MuPro (-0.76kcal/mol) have shown it to destabilize the protein. DynaMut2 also predicted a strong destabilization for the protein with the three variants together (-1.9kcal/mol), mimicking the proband's protein. However, experimental evidence is lacking. For the reasons above we have classified this variant as "Likely Pathogenic". -

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly850Arg in exon 20 of OTOG: This variant is not expected to have clinical sign ificance because it has been identified in 6.7% (13/194) of Luhya (Kenyan) chrom osomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm. nih.gov/projects/SNP; dbSNP rs61734214). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0065

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

3.5

M;.

PhyloP100

7.4

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-7.2

D;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.81

MutPred

0.52

Gain of catalytic residue at G850 (P = 0.0558);.;

MVP

0.56

ClinPred

0.087

GERP RS

5.2

Varity_R

0.84

gMVP

0.81

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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