rs7106548

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.2038T>C(p.Ser680Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,549,820 control chromosomes in the GnomAD database, including 150,699 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 (★★).

Frequency

Genomes: 𝑓 0.47 ( 17766 hom., cov: 31)

Exomes 𝑓: 0.43 ( 132933 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.125

Publications

21 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=1.3958546E-5).

BP6

Variant 11-17572162-T-C is Benign according to our data. Variant chr11-17572162-T-C is described in ClinVar as Benign. ClinVar VariationId is 226866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. 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.2038T>C	p.Ser680Pro	missense	Exon 18 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.2074T>C	p.Ser692Pro	missense	Exon 17 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.2038T>C	p.Ser680Pro	missense	Exon 18 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.2074T>C	p.Ser692Pro	missense	Exon 17 of 55	ENSP00000382323.2

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

71314

AN:

151694

Hom.:

17741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.628

Gnomad AMI

AF:

0.498

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.439

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.437

Gnomad OTH

AF:

0.437

GnomAD2 exomes

AF:

0.390

AC:

57374

AN:

146938

AF XY:

0.394

show subpopulations

Gnomad AFR exome

AF:

0.634

Gnomad AMR exome

AF:

0.247

Gnomad ASJ exome

AF:

0.446

Gnomad EAS exome

AF:

0.289

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.435

Gnomad OTH exome

AF:

0.397

GnomAD4 exome

AF:

0.432

AC:

604619

AN:

1398008

Hom.:

132933

Cov.:

AF XY:

0.431

AC XY:

297309

AN XY:

689536

show subpopulations

African (AFR)

AF:

0.634

AC:

20013

AN:

31590

American (AMR)

AF:

0.261

AC:

9305

AN:

35682

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

11162

AN:

25166

East Asian (EAS)

AF:

0.257

AC:

9166

AN:

35722

South Asian (SAS)

AF:

0.385

AC:

30477

AN:

79218

European-Finnish (FIN)

AF:

0.405

AC:

19514

AN:

48180

Middle Eastern (MID)

AF:

0.393

AC:

2237

AN:

5698

European-Non Finnish (NFE)

AF:

0.443

AC:

477836

AN:

1078774

Other (OTH)

AF:

0.430

AC:

24909

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

18956

37912

56869

75825

94781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14686

29372

44058

58744

73430

<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:

0.470

AC:

71385

AN:

151812

Hom.:

17766

Cov.:

AF XY:

0.465

AC XY:

34477

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.628

AC:

25964

AN:

41360

American (AMR)

AF:

0.338

AC:

5167

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.439

AC:

1522

AN:

3464

East Asian (EAS)

AF:

0.283

AC:

1448

AN:

5120

South Asian (SAS)

AF:

0.377

AC:

1815

AN:

4814

European-Finnish (FIN)

AF:

0.406

AC:

4280

AN:

10530

Middle Eastern (MID)

AF:

0.418

AC:

123

AN:

294

European-Non Finnish (NFE)

AF:

0.437

AC:

29700

AN:

67936

Other (OTH)

AF:

0.433

AC:

912

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1835

3669

5504

7338

9173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.450

Hom.:

36153

Bravo

AF:

0.468

TwinsUK

AF:

0.455

AC:

1687

ALSPAC

AF:

0.433

AC:

1667

ExAC

AF:

0.374

AC:

8364

Asia WGS

AF:

0.363

AC:

1265

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Autosomal recessive nonsyndromic hearing loss 18B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.049

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.067

MetaRNN

Benign

0.000014

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.94

PhyloP100

0.13

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.48

REVEL

Benign

0.017

Sift

Benign

0.46

Sift4G

Benign

0.32

Vest4

0.034

ClinPred

0.0017

GERP RS

-4.2

Varity_R

0.080

gMVP

0.40

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

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