11-17558236-C-A

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.917C>A(p.Ala306Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,550,482 control chromosomes in the GnomAD database, including 19,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A306N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1488 hom., cov: 32)

Exomes 𝑓: 0.16 ( 17924 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.951

Publications

10 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=8.969605E-4).

BP6

Variant 11-17558236-C-A is Benign according to our data. Variant chr11-17558236-C-A is described in ClinVar as Benign. ClinVar VariationId is 226925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.917C>A	p.Ala306Asp	missense_variant	Exon 9 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.953C>A	p.Ala318Asp	missense_variant	Exon 8 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.917C>A	p.Ala306Asp	missense_variant	Exon 9 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.953C>A	p.Ala318Asp	missense_variant	Exon 8 of 55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000498332.5 link	n.823C>A		non_coding_transcript_exon_variant	Exon 8 of 16	5
OTOG	ENST00000485669.1 link	n.405-226C>A		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19209

AN:

152100

Hom.:

1487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0529

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.0538

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.151

GnomAD2 exomes

AF:

0.144

AC:

21426

AN:

149176

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0470

Gnomad AMR exome

AF:

0.0914

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.0525

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.171

GnomAD4 exome

AF:

0.156

AC:

217519

AN:

1398264

Hom.:

17924

Cov.:

AF XY:

0.157

AC XY:

108577

AN XY:

689660

show subpopulations

African (AFR)

AF:

0.0523

AC:

1653

AN:

31598

American (AMR)

AF:

0.0969

AC:

3459

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6201

AN:

25178

East Asian (EAS)

AF:

0.0395

AC:

1410

AN:

35738

South Asian (SAS)

AF:

0.185

AC:

14692

AN:

79232

European-Finnish (FIN)

AF:

0.125

AC:

6013

AN:

48184

Middle Eastern (MID)

AF:

0.248

AC:

1412

AN:

5696

European-Non Finnish (NFE)

AF:

0.161

AC:

173553

AN:

1078928

Other (OTH)

AF:

0.157

AC:

9126

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

10708

21416

32124

42832

53540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6084

12168

18252

24336

30420

<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:

0.126

AC:

19205

AN:

152218

Hom.:

1488

Cov.:

AF XY:

0.124

AC XY:

9209

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0528

AC:

2195

AN:

41542

American (AMR)

AF:

0.119

AC:

1813

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

821

AN:

3470

East Asian (EAS)

AF:

0.0538

AC:

278

AN:

5170

South Asian (SAS)

AF:

0.179

AC:

863

AN:

4824

European-Finnish (FIN)

AF:

0.120

AC:

1277

AN:

10600

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.167

AC:

11351

AN:

67998

Other (OTH)

AF:

0.150

AC:

317

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

836

1672

2507

3343

4179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.142

Hom.:

1247

Bravo

AF:

0.119

TwinsUK

AF:

0.153

AC:

566

ALSPAC

AF:

0.156

AC:

602

ExAC

AF:

0.136

AC:

3130

Asia WGS

AF:

0.129

AC:

452

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 03, 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. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala318Asp in exon 8 of OTOG: This variant is not expected to have clinical signi ficance because it has been identified in 23.0% (45/196) of Toscan chromosomes f rom a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/ projects/SNP; dbSNP rs61611064). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.51

T;T

MetaRNN

Benign

0.00090

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.44

N;.

PhyloP100

0.95

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.035

Sift

Benign

0.21

T;.

Sift4G

Uncertain

0.060

T;T

Vest4

0.10

ClinPred

0.0030

GERP RS

1.7

Varity_R

0.12

gMVP

0.51

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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