11-17606066-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001292063.2(OTOG):c.4087G>C(p.Ala1363Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,550,206 control chromosomes in the GnomAD database, including 412,865 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1363A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.79 ( 48159 hom., cov: 35)

Exomes 𝑓: 0.72 ( 364706 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.242

Publications

19 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.67201E-6).

BP6

Variant 11-17606066-G-C is Benign according to our data. Variant chr11-17606066-G-C is described in ClinVar as Benign. ClinVar VariationId is 226892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.4087G>C	p.Ala1363Pro	missense_variant	Exon 33 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.4123G>C	p.Ala1375Pro	missense_variant	Exon 32 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OTOG	ENST00000399397.6 link	c.4087G>C	p.Ala1363Pro	missense_variant	Exon 33 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.4123G>C	p.Ala1375Pro	missense_variant	Exon 32 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2 link	n.1425G>C		non_coding_transcript_exon_variant	Exon 9 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.787

AC:

119730

AN:

152112

Hom.:

48097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.947

Gnomad AMI

AF:

0.616

Gnomad AMR

AF:

0.775

Gnomad ASJ

AF:

0.848

Gnomad EAS

AF:

0.825

Gnomad SAS

AF:

0.760

Gnomad FIN

AF:

0.697

Gnomad MID

AF:

0.845

Gnomad NFE

AF:

0.704

Gnomad OTH

AF:

0.796

GnomAD2 exomes

AF:

0.755

AC:

111267

AN:

147448

AF XY:

0.753

show subpopulations

Gnomad AFR exome

AF:

0.954

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.837

Gnomad EAS exome

AF:

0.838

Gnomad FIN exome

AF:

0.699

Gnomad NFE exome

AF:

0.711

Gnomad OTH exome

AF:

0.758

GnomAD4 exome

AF:

0.720

AC:

1006907

AN:

1397976

Hom.:

364706

Cov.:

AF XY:

0.721

AC XY:

497023

AN XY:

689478

show subpopulations

African (AFR)

AF:

0.959

AC:

30290

AN:

31594

American (AMR)

AF:

0.764

AC:

27260

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.843

AC:

21224

AN:

25168

East Asian (EAS)

AF:

0.803

AC:

28701

AN:

35732

South Asian (SAS)

AF:

0.754

AC:

59752

AN:

79218

European-Finnish (FIN)

AF:

0.691

AC:

33231

AN:

48080

Middle Eastern (MID)

AF:

0.842

AC:

4755

AN:

5648

European-Non Finnish (NFE)

AF:

0.703

AC:

758168

AN:

1078872

Other (OTH)

AF:

0.751

AC:

43526

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

18324

36648

54972

73296

91620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19464

38928

58392

77856

97320

<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:

0.787

AC:

119850

AN:

152230

Hom.:

48159

Cov.:

AF XY:

0.787

AC XY:

58561

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.947

AC:

39364

AN:

41572

American (AMR)

AF:

0.775

AC:

11860

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.848

AC:

2943

AN:

3472

East Asian (EAS)

AF:

0.826

AC:

4265

AN:

5166

South Asian (SAS)

AF:

0.760

AC:

3668

AN:

4826

European-Finnish (FIN)

AF:

0.697

AC:

7382

AN:

10596

Middle Eastern (MID)

AF:

0.861

AC:

253

AN:

294

European-Non Finnish (NFE)

AF:

0.704

AC:

47877

AN:

67980

Other (OTH)

AF:

0.794

AC:

1677

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1253

2506

3758

5011

6264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.711

Hom.:

10187

Bravo

AF:

0.801

TwinsUK

AF:

0.702

AC:

2603

ExAC

AF:

0.716

AC:

14213

Asia WGS

AF:

0.791

AC:

2753

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 23, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala1375Pro in exon 32 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 100.0% (194/194) of Luhya (Kenyan) c hromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi. nlm.nih.gov/projects/SNP; dbSNP rs7934079).

May 09, 2017

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Autosomal recessive nonsyndromic hearing loss 18B

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.4

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.040

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

LIST_S2

Benign

0.38

T;T

MetaRNN

Benign

0.0000017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.

PhyloP100

0.24

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.10

N;.

Sift

Benign

0.31

T;.

Sift4G

Benign

0.41

T;T

Vest4

0.070

ClinPred

0.0034

GERP RS

3.0

Varity_R

0.078

gMVP

0.62

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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