rs1295062471

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001292063.2(OTOG):c.7481-5_7482dupGCCAGTG(p.Cys2495fs) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000539 in 1,548,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 frameshift, splice_region

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:1

Conservation

PhyloP100: 1.07

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: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.7481-5_7482dupGCCAGTG	p.Cys2495fs	frameshift_variant, splice_region_variant	Exon 45 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.7517-5_7518dupGCCAGTG	p.Cys2507fs	frameshift_variant, splice_region_variant	Exon 44 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.7481-7_7481-6insGGCCAGT	splice_region_variant, intron_variant	Intron 44 of 55	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.7517-7_7517-6insGGCCAGT	splice_region_variant, intron_variant	Intron 43 of 54	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.4606-773_4606-772insGGCCAGT	intron_variant	Intron 19 of 21	2

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000384

AC:

AN:

145702

AF XY:

0.000344

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000972

Gnomad OTH exome

AF:

0.000237

GnomAD4 exome

AF:

0.000563

AC:

786

AN:

1396630

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

390

AN XY:

688786

show subpopulations

African (AFR)

AF:

0.0000634

AC:

AN:

31566

American (AMR)

AF:

0.000112

AC:

AN:

35650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25126

East Asian (EAS)

AF:

0.00

AC:

AN:

35730

South Asian (SAS)

AF:

0.00

AC:

AN:

79110

European-Finnish (FIN)

AF:

0.000104

AC:

AN:

48132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5134

European-Non Finnish (NFE)

AF:

0.000702

AC:

757

AN:

1078316

Other (OTH)

AF:

0.000311

AC:

AN:

57866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000322

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.000325

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 05, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified with a second OTOG variant, phase unknown, in a patient with moderate sporadic hearing loss in the published literature (PMID: 32860223); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32860223, 34515852) -

Autosomal recessive nonsyndromic hearing loss 18B

Pathogenic:2

Mar 18, 2021

King Laboratory, University of Washington

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

OTOG c.7517-5_7518dup is predicted to introduce a cryptic splice acceptor within the sequence of the in-tandem duplication in OTOG intron 43. The cryptic splice acceptor in OTOG intron 43 occurs upstream of the OTOG exon 44 canonical splice and is predicted to result in inclusion of the mutant exon with the 7bp duplication leading to a premature stop. Consequence of this in-tandem duplication would be splicing of OTOG exon 44 occurring at the cryptic splice acceptor and resulting in a 7bp insertion in the OTOG message and premature stop at codon 2510 of 2926. -

Nov 17, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7517-5_7518dup variant in OTOG has been previously reported in one individ ual with hearing loss; however, a variant affecting the remaining copy of OTOG w as not detected in this individual and an alternate genetic explanation for thei r disease was identified(LMM unpublished data). Data from large population studi es is insufficient to assess the frequency of this variant. This variant is a ta ndem duplication of 7 base pairs that encompass the 3' splice junction of intron 43 in the OTOG gene. However, it is not clear whether this will result in splic ing to occur at a novel 3' splice site downstream of the nascent splice site, wh ich would not impact the protein, or if splicing occurs at the nascent splice si te, which would result in a frameshift of the coding sequence and therefore, be deleterious to the protein. Computational tools predict that splicing would occu r at the novel 3' splice site and thus would not result in a frameshift of the c oding sequence; however, functional studies are needed to determine which of the se scenarios is correct. In summary, the clinical significance of the c.7517-5_7 518dup variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs1295062471

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