NM_001292063.2:c.8476C>T

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.8476C>T(p.Arg2826Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00255 in 1,550,572 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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. R2826H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 11 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.92

Publications

7 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 links:

LINC02729 (HGNC:54246): (long intergenic non-protein coding RNA 2729)

LINC02729 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=0.008724064).

BP6

Variant 11-17645578-C-T is Benign according to our data. Variant chr11-17645578-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218586.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00211 (322/152334) while in subpopulation NFE AF = 0.00315 (214/68022). AF 95% confidence interval is 0.0028. There are 1 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.8476C>T	p.Arg2826Cys	missense_variant	Exon 55 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.8512C>T	p.Arg2838Cys	missense_variant	Exon 54 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.8476C>T	p.Arg2826Cys	missense_variant	Exon 55 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.8512C>T	p.Arg2838Cys	missense_variant	Exon 54 of 55	5		ENSP00000382323.2	Q6ZRI0-1
LINC02729	ENST00000849122.1 link	n.196-505G>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

323

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00217

AC:

323

AN:

148796

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00503

Gnomad EAS exome

AF:

0.000464

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.00260

AC:

3634

AN:

1398238

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1738

AN XY:

689638

show subpopulations

African (AFR)

AF:

0.000285

AC:

AN:

31598

American (AMR)

AF:

0.000896

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00520

AC:

131

AN:

25176

East Asian (EAS)

AF:

0.000616

AC:

AN:

35736

South Asian (SAS)

AF:

0.00237

AC:

188

AN:

79218

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

48168

Middle Eastern (MID)

AF:

0.00509

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00280

AC:

3018

AN:

1078948

Other (OTH)

AF:

0.00210

AC:

122

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

196

392

589

785

981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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:

0.00211

AC:

322

AN:

152334

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41582

American (AMR)

AF:

0.000588

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00248

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00226

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00315

AC:

214

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00181

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.00157

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OTOG: BS1, BS2 -

not specified

Uncertain:1Benign:1

Jul 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 24, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg2838Cys in exon 54 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (20/5018) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191662816). -

OTOG-related disorder

Benign:1

Nov 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

PhyloP100

4.9

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.2

D;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.44

MVP

0.52

ClinPred

0.074

GERP RS

3.0

Varity_R

0.45

gMVP

0.54

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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