11-17645578-C-T

Position:

chr11-17645578-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_001292063.2(OTOG):c.8476C>T(p.Arg2826Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00255 in 1,550,572 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2826H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 11 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.92

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17645579-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.008724064).

BP6

Variant 11-17645578-C-T is Benign according to our data. Variant chr11-17645578-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218586.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.8476C>T	p.Arg2826Cys	missense_variant	55/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 linkuse as main transcript	c.8512C>T	p.Arg2838Cys	missense_variant	54/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.8476C>T	p.Arg2826Cys	missense_variant	55/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.8512C>T	p.Arg2838Cys	missense_variant	54/55	5		ENSP00000382323	A2	Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

323

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00226

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00217

AC:

323

AN:

148796

Hom.:

AF XY:

0.00222

AC XY:

178

AN XY:

80154

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00503

Gnomad EAS exome

AF:

0.000464

Gnomad SAS exome

AF:

0.00204

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00304

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.00260

AC:

3634

AN:

1398238

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1738

AN XY:

689638

show subpopulations

Gnomad4 AFR exome

AF:

0.000285

Gnomad4 AMR exome

AF:

0.000896

Gnomad4 ASJ exome

AF:

0.00520

Gnomad4 EAS exome

AF:

0.000616

Gnomad4 SAS exome

AF:

0.00237

Gnomad4 FIN exome

AF:

0.00172

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00211

AC:

322

AN:

152334

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00226

Gnomad4 NFE

AF:

0.00315

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00235

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ExAC

AF:

0.00157

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	OTOG: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2023	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 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2015	p.Arg2838Cys in exon 54 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (20/5018) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191662816). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 17, 2015	- -

OTOG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.2

D;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.44

MVP

0.52

ClinPred

0.074

GERP RS

3.0

Varity_R

0.45

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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