rs142799217

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_001292063.2(OTOG):c.6893G>A(p.Arg2298His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,550,382 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.29

Publications

2 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010238647).

BP6

Variant 11-17631882-G-A is Benign according to our data. Variant chr11-17631882-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229098.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00198 (302/152330) while in subpopulation AFR AF = 0.00683 (284/41574). AF 95% confidence interval is 0.00618. There are 0 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.6893G>A	p.Arg2298His	missense_variant	Exon 41 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.6929G>A	p.Arg2310His	missense_variant	Exon 40 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OTOG	ENST00000399397.6 link	c.6893G>A	p.Arg2298His	missense_variant	Exon 41 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.6929G>A	p.Arg2310His	missense_variant	Exon 40 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2 link	n.4231G>A		non_coding_transcript_exon_variant	Exon 17 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

293

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00663

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.000525

AC:

AN:

148628

AF XY:

0.000437

show subpopulations

Gnomad AFR exome

AF:

0.00857

Gnomad AMR exome

AF:

0.000692

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000195

AC:

272

AN:

1398052

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

119

AN XY:

689554

show subpopulations

African (AFR)

AF:

0.00684

AC:

216

AN:

31598

American (AMR)

AF:

0.000728

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47970

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1078974

Other (OTH)

AF:

0.000345

AC:

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00198

AC:

302

AN:

152330

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00683

AC:

284

AN:

41574

American (AMR)

AF:

0.000588

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000824

Hom.:

Bravo

AF:

0.00225

ExAC

AF:

0.000248

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jun 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 18, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 22, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg2310His in exon 40 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.75% (114/15242) of African chrom osomes, including one homozygote, by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/; dbSNP rs142799217). ACMG/AMP Criteria applied: BA1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.033

T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.81

L;.

PhyloP100

2.3

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.26

Sift

Benign

0.074

T;.

Sift4G

Uncertain

0.027

D;D

Vest4

0.21

MVP

0.60

ClinPred

0.066

GERP RS

4.8

Varity_R

0.060

gMVP

0.35

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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