11-17606066-G-C

Position:

chr11-17606066-G-C

Variant summary

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

The NM_001292063.2(OTOG):c.4087G>C(p.Ala1363Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,550,206 control chromosomes in the GnomAD database, including 412,865 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 0.79 ( 48159 hom., cov: 35)

Exomes 𝑓: 0.72 ( 364706 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.242

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=1.67201E-6).

BP6

Variant 11-17606066-G-C is Benign according to our data. Variant chr11-17606066-G-C is described in ClinVar as [Benign]. Clinvar id is 226892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17606066-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.4087G>C	p.Ala1363Pro	missense_variant	33/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 linkuse as main transcript	c.4123G>C	p.Ala1375Pro	missense_variant	32/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.4087G>C	p.Ala1363Pro	missense_variant	33/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.4123G>C	p.Ala1375Pro	missense_variant	32/55	5		ENSP00000382323	A2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.1425G>C		non_coding_transcript_exon_variant	9/22	2

Frequencies

GnomAD3 genomes

AF:

0.787

AC:

119730

AN:

152112

Hom.:

48097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.947

Gnomad AMI

AF:

0.616

Gnomad AMR

AF:

0.775

Gnomad ASJ

AF:

0.848

Gnomad EAS

AF:

0.825

Gnomad SAS

AF:

0.760

Gnomad FIN

AF:

0.697

Gnomad MID

AF:

0.845

Gnomad NFE

AF:

0.704

Gnomad OTH

AF:

0.796

GnomAD3 exomes

AF:

0.755

AC:

111267

AN:

147448

Hom.:

42320

AF XY:

0.753

AC XY:

59886

AN XY:

79520

show subpopulations

Gnomad AFR exome

AF:

0.954

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.837

Gnomad EAS exome

AF:

0.838

Gnomad SAS exome

AF:

0.753

Gnomad FIN exome

AF:

0.699

Gnomad NFE exome

AF:

0.711

Gnomad OTH exome

AF:

0.758

GnomAD4 exome

AF:

0.720

AC:

1006907

AN:

1397976

Hom.:

364706

Cov.:

AF XY:

0.721

AC XY:

497023

AN XY:

689478

show subpopulations

Gnomad4 AFR exome

AF:

0.959

Gnomad4 AMR exome

AF:

0.764

Gnomad4 ASJ exome

AF:

0.843

Gnomad4 EAS exome

AF:

0.803

Gnomad4 SAS exome

AF:

0.754

Gnomad4 FIN exome

AF:

0.691

Gnomad4 NFE exome

AF:

0.703

Gnomad4 OTH exome

AF:

0.751

GnomAD4 genome

AF:

0.787

AC:

119850

AN:

152230

Hom.:

48159

Cov.:

AF XY:

0.787

AC XY:

58561

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.947

Gnomad4 AMR

AF:

0.775

Gnomad4 ASJ

AF:

0.848

Gnomad4 EAS

AF:

0.826

Gnomad4 SAS

AF:

0.760

Gnomad4 FIN

AF:

0.697

Gnomad4 NFE

AF:

0.704

Gnomad4 OTH

AF:

0.794

Alfa

AF:

0.711

Hom.:

10187

Bravo

AF:

0.801

TwinsUK

AF:

0.702

AC:

2603

ALSPAC

AF:

0.696

AC:

2684

ExAC

AF:

0.716

AC:

14213

Asia WGS

AF:

0.791

AC:

2753

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ala1375Pro in exon 32 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 100.0% (194/194) of Luhya (Kenyan) c hromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi. nlm.nih.gov/projects/SNP; dbSNP rs7934079). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2017	- -

not provided

Benign:2

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

Autosomal recessive nonsyndromic hearing loss 18B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.4

DANN

Benign

0.76

DEOGEN2

Benign

0.040

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.38

T;T

MetaRNN

Benign

0.0000017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.10

N;.

REVEL

Benign

0.032

Sift

Benign

0.31

T;.

Sift4G

Benign

0.41

T;T

Vest4

0.070

ClinPred

0.0034

GERP RS

3.0

Varity_R

0.078

gMVP

0.62

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