11-17610204-C-T

Position:

chr11-17610204-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001292063.2(OTOG):c.4904C>T(p.Pro1635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,550,170 control chromosomes in the GnomAD database, including 115,879 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 15276 hom., cov: 32)

Exomes 𝑓: 0.37 ( 100603 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.102

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.881634E-6).

BP6

Variant 11-17610204-C-T is Benign according to our data. Variant chr11-17610204-C-T is described in ClinVar as [Benign]. Clinvar id is 226895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17610204-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.4904C>T	p.Pro1635Leu	missense_variant	36/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.4940C>T	p.Pro1647Leu	missense_variant	35/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OTOG	ENST00000399397.6 link	c.4904C>T	p.Pro1635Leu	missense_variant	36/56	5	NM_001292063.2	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7 link	c.4940C>T	p.Pro1647Leu	missense_variant	35/55	5		ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2 link	n.2242C>T		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65198

AN:

151866

Hom.:

15251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.624

Gnomad AMI

AF:

0.441

Gnomad AMR

AF:

0.314

Gnomad ASJ

AF:

0.330

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.373

Gnomad OTH

AF:

0.391

GnomAD3 exomes

AF:

0.353

AC:

52585

AN:

149160

Hom.:

10086

AF XY:

0.360

AC XY:

28906

AN XY:

80294

show subpopulations

Gnomad AFR exome

AF:

0.635

Gnomad AMR exome

AF:

0.221

Gnomad ASJ exome

AF:

0.342

Gnomad EAS exome

AF:

0.212

Gnomad SAS exome

AF:

0.446

Gnomad FIN exome

AF:

0.340

Gnomad NFE exome

AF:

0.372

Gnomad OTH exome

AF:

0.333

GnomAD4 exome

AF:

0.374

AC:

522758

AN:

1398186

Hom.:

100603

Cov.:

AF XY:

0.375

AC XY:

258806

AN XY:

689618

show subpopulations

Gnomad4 AFR exome

AF:

0.631

Gnomad4 AMR exome

AF:

0.233

Gnomad4 ASJ exome

AF:

0.338

Gnomad4 EAS exome

AF:

0.194

Gnomad4 SAS exome

AF:

0.444

Gnomad4 FIN exome

AF:

0.337

Gnomad4 NFE exome

AF:

0.375

Gnomad4 OTH exome

AF:

0.372

GnomAD4 genome

AF:

0.429

AC:

65264

AN:

151984

Hom.:

15276

Cov.:

AF XY:

0.426

AC XY:

31631

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.624

Gnomad4 AMR

AF:

0.314

Gnomad4 ASJ

AF:

0.330

Gnomad4 EAS

AF:

0.202

Gnomad4 SAS

AF:

0.460

Gnomad4 FIN

AF:

0.333

Gnomad4 NFE

AF:

0.373

Gnomad4 OTH

AF:

0.391

Alfa

AF:

0.368

Hom.:

14877

Bravo

AF:

0.428

TwinsUK

AF:

0.376

AC:

1396

ALSPAC

AF:

0.365

AC:

1407

ExAC

AF:

0.313

AC:

8096

Asia WGS

AF:

0.372

AC:

1294

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro1647Leu in exon 35 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 63.6% (112/176) of Yoruba (Nigerian) chromosomes from a broad population by the 1000 Genomes Project (http://www.ncb i.nlm.nih.gov/projects/SNP; dbSNP rs2041028). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.0

DANN

Benign

0.13

DEOGEN2

Benign

0.017

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0000089

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.4

N;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.059

Sift

Benign

0.59

T;D

Sift4G

Benign

0.44

T;T

Vest4

0.076

ClinPred

0.0053

GERP RS

4.1

Varity_R

0.025

gMVP

0.20

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

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