11-17645592-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001292063.2(OTOG):c.8490G>C(p.Lys2830Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,550,656 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 32 hom., cov: 33)

Exomes 𝑓: 0.019 ( 296 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.82

Publications

7 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 links:

LINC02729 (HGNC:54246): (long intergenic non-protein coding RNA 2729)

LINC02729 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=0.0055775344).

BP6

Variant 11-17645592-G-C is Benign according to our data. Variant chr11-17645592-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0156 (2381/152358) while in subpopulation NFE AF = 0.0234 (1591/68022). AF 95% confidence interval is 0.0224. There are 32 homozygotes in GnomAd4. There are 1135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.8490G>C	p.Lys2830Asn	missense_variant	Exon 55 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.8526G>C	p.Lys2842Asn	missense_variant	Exon 54 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.8490G>C	p.Lys2830Asn	missense_variant	Exon 55 of 56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.8526G>C	p.Lys2842Asn	missense_variant	Exon 54 of 55	5		ENSP00000382323.2	Q6ZRI0-1
LINC02729	ENST00000849122.1 link	n.196-519C>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2382

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0258

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0234

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0149

AC:

2218

AN:

149002

AF XY:

0.0142

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00940

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0187

AC:

26133

AN:

1398298

Hom.:

296

Cov.:

AF XY:

0.0182

AC XY:

12552

AN XY:

689672

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

31598

American (AMR)

AF:

0.0104

AC:

371

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

461

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00175

AC:

139

AN:

79236

European-Finnish (FIN)

AF:

0.0294

AC:

1418

AN:

48164

Middle Eastern (MID)

AF:

0.00614

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0211

AC:

22761

AN:

1078976

Other (OTH)

AF:

0.0149

AC:

865

AN:

58002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1539

3079

4618

6158

7697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

830

1660

2490

3320

4150

<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:

0.0156

AC:

2381

AN:

152358

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1135

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41588

American (AMR)

AF:

0.0115

AC:

176

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0258

AC:

274

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0234

AC:

1591

AN:

68022

Other (OTH)

AF:

0.0156

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0182

Hom.:

Bravo

AF:

0.0150

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0234

AC:

ExAC

AF:

0.00794

AC:

181

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 02, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lys2842Asn in exon 54 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 3.8% (7/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs61997203). -

Meniere disease

Benign:1

Jan 01, 2020

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Benign

-0.0055

Eigen_PC

Benign

0.0050

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0056

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

PhyloP100

1.8

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.0

D;.

REVEL

Benign

0.11

Sift

Uncertain

0.0020

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.51

MutPred

0.31

Loss of methylation at K2842 (P = 0.0301);.;

ClinPred

0.015

GERP RS

1.2

Varity_R

0.65

gMVP

0.56

Mutation Taster

=83/17

polymorphism

(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