rs876657944

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001292063.2(OTOG):c.7810C>T(p.Arg2604Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000323 in 1,549,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.89

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.7810C>T	p.Arg2604Cys	missense_variant	Exon 48 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.7846C>T	p.Arg2616Cys	missense_variant	Exon 47 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OTOG	ENST00000399397.6 link	c.7810C>T	p.Arg2604Cys	missense_variant	Exon 48 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.7846C>T	p.Arg2616Cys	missense_variant	Exon 47 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2 link	n.4722C>T		non_coding_transcript_exon_variant	Exon 21 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000204

AC:

AN:

147342

AF XY:

0.0000378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.0000243

AC:

AN:

1396884

Hom.:

Cov.:

AF XY:

0.0000203

AC XY:

AN XY:

689018

show subpopulations

African (AFR)

AF:

0.0000950

AC:

AN:

31588

American (AMR)

AF:

0.000112

AC:

AN:

35642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25156

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.000114

AC:

AN:

79174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

1078830

Other (OTH)

AF:

0.0000690

AC:

AN:

57978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000105

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41438

American (AMR)

AF:

0.000785

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000283

Hom.:

Bravo

AF:

0.000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 22, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg2616Cys variant in OTOG has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that the Arg2616Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, th e clinical significance of the p.Arg2616Cys variant is uncertain. -

not provided

Uncertain:1

Dec 19, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.

PhyloP100

3.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.1

N;.

REVEL

Benign

0.22

Sift

Uncertain

0.027

D;.

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.49

MutPred

0.56

Loss of catalytic residue at R2616 (P = 0.1314);.;

MVP

0.53

ClinPred

0.51

GERP RS

5.4

Varity_R

0.24

gMVP

0.91

Mutation Taster

=78/22

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over