rs2355466

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.2719G>A(p.Ala907Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,539,508 control chromosomes in the GnomAD database, including 110,619 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 0.32 ( 8488 hom., cov: 33)

Exomes 𝑓: 0.38 ( 102131 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.75

Publications

18 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=0.006000221).

BP6

Variant 11-17578486-G-A is Benign according to our data. Variant chr11-17578486-G-A is described in ClinVar as Benign. ClinVar VariationId is 226873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.394 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.2719G>A	p.Ala907Thr	missense	Exon 23 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.2755G>A	p.Ala919Thr	missense	Exon 22 of 55	NP_001264198.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OTOG	ENST00000399397.6	TSL:5 MANE Select	c.2719G>A	p.Ala907Thr	missense	Exon 23 of 56	ENSP00000382329.2
OTOG	ENST00000399391.7	TSL:5	c.2755G>A	p.Ala919Thr	missense	Exon 22 of 55	ENSP00000382323.2
OTOG	ENST00000342528.2	TSL:2	n.223G>A		non_coding_transcript_exon	Exon 1 of 22

Frequencies

GnomAD3 genomes

AF:

0.322

AC:

48915

AN:

152028

Hom.:

8484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.398

Gnomad OTH

AF:

0.323

GnomAD2 exomes

AF:

0.323

AC:

45053

AN:

139384

AF XY:

0.331

show subpopulations

Gnomad AFR exome

AF:

0.215

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.384

Gnomad EAS exome

AF:

0.230

Gnomad FIN exome

AF:

0.382

Gnomad NFE exome

AF:

0.397

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.380

AC:

527054

AN:

1387362

Hom.:

102131

Cov.:

AF XY:

0.379

AC XY:

259596

AN XY:

684652

show subpopulations

African (AFR)

AF:

0.220

AC:

6933

AN:

31584

American (AMR)

AF:

0.196

AC:

6978

AN:

35662

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

9550

AN:

25162

East Asian (EAS)

AF:

0.205

AC:

7321

AN:

35720

South Asian (SAS)

AF:

0.324

AC:

25636

AN:

79176

European-Finnish (FIN)

AF:

0.371

AC:

14003

AN:

37746

Middle Eastern (MID)

AF:

0.343

AC:

1950

AN:

5686

European-Non Finnish (NFE)

AF:

0.402

AC:

433636

AN:

1078704

Other (OTH)

AF:

0.363

AC:

21047

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

18371

36743

55114

73486

91857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13508

27016

40524

54032

67540

<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:

0.322

AC:

48933

AN:

152146

Hom.:

8488

Cov.:

AF XY:

0.320

AC XY:

23788

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.220

AC:

9130

AN:

41516

American (AMR)

AF:

0.241

AC:

3689

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

1309

AN:

3472

East Asian (EAS)

AF:

0.221

AC:

1141

AN:

5166

South Asian (SAS)

AF:

0.318

AC:

1533

AN:

4816

European-Finnish (FIN)

AF:

0.368

AC:

3911

AN:

10614

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.398

AC:

27052

AN:

67950

Other (OTH)

AF:

0.320

AC:

676

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1698

3396

5094

6792

8490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

492

984

1476

1968

2460

<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:

0.349

Hom.:

5346

Bravo

AF:

0.306

TwinsUK

AF:

0.406

AC:

1506

ALSPAC

AF:

0.391

AC:

1506

ExAC

AF:

0.300

AC:

6070

Asia WGS

AF:

0.283

AC:

987

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

0.072

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.049

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.21

PhyloP100

2.7

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.82

REVEL

Benign

0.070

Sift

Benign

0.25

Sift4G

Benign

0.48

Vest4

0.037

ClinPred

0.0061

GERP RS

4.9

Varity_R

0.056

gMVP

0.25

Mutation Taster

=292/8

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