11-17634201-G-A

Variant names:

Variant summary

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

The ENST00000399397.6(OTOG):c.7400G>A(p.Arg2467His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,550,382 control chromosomes in the GnomAD database, including 1,366 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 (★★).

Frequency

Genomes: 𝑓 0.037 ( 118 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1248 hom. )

Consequence

OTOG
ENST00000399397.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.11

Publications

3 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=0.0020101964).

BP6

Variant 11-17634201-G-A is Benign according to our data. Variant chr11-17634201-G-A is described in ClinVar as Benign. ClinVar VariationId is 226908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399397.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.7400G>A	p.Arg2467His	missense	Exon 44 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.7436G>A	p.Arg2479His	missense	Exon 43 of 55	NP_001264198.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOG	ENST00000399397.6	TSL:5 MANE Select	c.7400G>A	p.Arg2467His	missense	Exon 44 of 56	ENSP00000382329.2
OTOG	ENST00000399391.7	TSL:5	c.7436G>A	p.Arg2479His	missense	Exon 43 of 55	ENSP00000382323.2
OTOG	ENST00000342528.2	TSL:2	n.4605+327G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5627

AN:

152108

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0376

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0517

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.0873

Gnomad FIN

AF:

0.0345

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0341

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.0405

AC:

5947

AN:

146874

AF XY:

0.0426

show subpopulations

Gnomad AFR exome

AF:

0.0334

Gnomad AMR exome

AF:

0.0432

Gnomad ASJ exome

AF:

0.0259

Gnomad EAS exome

AF:

0.00195

Gnomad FIN exome

AF:

0.0340

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0342

GnomAD4 exome

AF:

0.0386

AC:

54026

AN:

1398156

Hom.:

1248

Cov.:

AF XY:

0.0399

AC XY:

27491

AN XY:

689606

show subpopulations

African (AFR)

AF:

0.0367

AC:

1158

AN:

31594

American (AMR)

AF:

0.0418

AC:

1494

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

638

AN:

25182

East Asian (EAS)

AF:

0.00151

AC:

AN:

35738

South Asian (SAS)

AF:

0.0846

AC:

6705

AN:

79226

European-Finnish (FIN)

AF:

0.0313

AC:

1505

AN:

48132

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0375

AC:

40458

AN:

1078946

Other (OTH)

AF:

0.0337

AC:

1951

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3319

6637

9956

13274

16593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1662

3324

4986

6648

8310

<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:

0.0370

AC:

5636

AN:

152226

Hom.:

118

Cov.:

AF XY:

0.0388

AC XY:

2887

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0375

AC:

1559

AN:

41544

American (AMR)

AF:

0.0519

AC:

794

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3472

East Asian (EAS)

AF:

0.00251

AC:

AN:

5172

South Asian (SAS)

AF:

0.0878

AC:

423

AN:

4820

European-Finnish (FIN)

AF:

0.0345

AC:

366

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0341

AC:

2321

AN:

67984

Other (OTH)

AF:

0.0270

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

284

568

852

1136

1420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0342

Hom.:

129

Bravo

AF:

0.0347

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0374

AC:

144

ExAC

AF:

0.0445

AC:

927

Asia WGS

AF:

0.0640

AC:

223

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.080

REVEL

Benign

0.059

Sift

Benign

0.22

Sift4G

Benign

0.67

Vest4

0.028

ClinPred

0.0037

GERP RS

2.8

Varity_R

0.041

gMVP

0.39

Mutation Taster

=96/4

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over