rs117315845

Positions:

chr11-17642200-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001292063.2(OTOG):c.8369G>A(p.Arg2790His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,550,166 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 10 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062504113).

BP6

Variant 11-17642200-G-A is Benign according to our data. Variant chr11-17642200-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226920.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr11-17642200-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.8369G>A	p.Arg2790His	missense_variant	53/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.8405G>A	p.Arg2802His	missense_variant	52/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.8369G>A	p.Arg2790His	missense_variant	53/56	5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.8405G>A	p.Arg2802His	missense_variant	52/55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

311

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00261

AC:

384

AN:

147302

Hom.:

AF XY:

0.00271

AC XY:

215

AN XY:

79378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.0000928

Gnomad SAS exome

AF:

0.00262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00289

Gnomad OTH exome

AF:

0.00422

GnomAD4 exome

AF:

0.00233

AC:

3258

AN:

1397870

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1587

AN XY:

689454

show subpopulations

Gnomad4 AFR exome

AF:

0.000506

Gnomad4 AMR exome

AF:

0.00289

Gnomad4 ASJ exome

AF:

0.0118

Gnomad4 EAS exome

AF:

0.0000840

Gnomad4 SAS exome

AF:

0.00251

Gnomad4 FIN exome

AF:

0.0000208

Gnomad4 NFE exome

AF:

0.00224

Gnomad4 OTH exome

AF:

0.00314

GnomAD4 genome

AF:

0.00204

AC:

311

AN:

152296

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00253

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00302

Hom.:

Bravo

AF:

0.00232

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.00281

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	OTOG: BP4 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Meniere disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

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)

Jan 01, 2020

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 08, 2015

p.Arg2802His in exon 52 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (54/14664) of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 117315845). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.070

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.79

N;.

REVEL

Benign

0.059

Sift

Benign

0.23

T;.

Sift4G

Uncertain

0.032

D;D

Vest4

0.12

MVP

0.10

ClinPred

0.017

GERP RS

1.8

Varity_R

0.038

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over