rs7106548

Positions:

chr11-17572162-T-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.2038T>C(p.Ser680Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,549,820 control chromosomes in the GnomAD database, including 150,699 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 0.47 ( 17766 hom., cov: 31)

Exomes 𝑓: 0.43 ( 132933 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.125

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=1.3958546E-5).

BP6

Variant 11-17572162-T-C is Benign according to our data. Variant chr11-17572162-T-C is described in ClinVar as [Benign]. Clinvar id is 226866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17572162-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 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.2038T>C	p.Ser680Pro	missense_variant	18/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 linkuse as main transcript	c.2074T>C	p.Ser692Pro	missense_variant	17/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.2038T>C	p.Ser680Pro	missense_variant	18/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.2074T>C	p.Ser692Pro	missense_variant	17/55	5		ENSP00000382323	A2	Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

71314

AN:

151694

Hom.:

17741

Cov.:

show subpopulations

Gnomad AFR

AF:

0.628

Gnomad AMI

AF:

0.498

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.439

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.437

Gnomad OTH

AF:

0.437

GnomAD3 exomes

AF:

0.390

AC:

57374

AN:

146938

Hom.:

11892

AF XY:

0.394

AC XY:

31206

AN XY:

79252

show subpopulations

Gnomad AFR exome

AF:

0.634

Gnomad AMR exome

AF:

0.247

Gnomad ASJ exome

AF:

0.446

Gnomad EAS exome

AF:

0.289

Gnomad SAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.435

Gnomad OTH exome

AF:

0.397

GnomAD4 exome

AF:

0.432

AC:

604619

AN:

1398008

Hom.:

132933

Cov.:

AF XY:

0.431

AC XY:

297309

AN XY:

689536

show subpopulations

Gnomad4 AFR exome

AF:

0.634

Gnomad4 AMR exome

AF:

0.261

Gnomad4 ASJ exome

AF:

0.444

Gnomad4 EAS exome

AF:

0.257

Gnomad4 SAS exome

AF:

0.385

Gnomad4 FIN exome

AF:

0.405

Gnomad4 NFE exome

AF:

0.443

Gnomad4 OTH exome

AF:

0.430

GnomAD4 genome

AF:

0.470

AC:

71385

AN:

151812

Hom.:

17766

Cov.:

AF XY:

0.465

AC XY:

34477

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.628

Gnomad4 AMR

AF:

0.338

Gnomad4 ASJ

AF:

0.439

Gnomad4 EAS

AF:

0.283

Gnomad4 SAS

AF:

0.377

Gnomad4 FIN

AF:

0.406

Gnomad4 NFE

AF:

0.437

Gnomad4 OTH

AF:

0.433

Alfa

AF:

0.441

Hom.:

25527

Bravo

AF:

0.468

TwinsUK

AF:

0.455

AC:

1687

ALSPAC

AF:

0.433

AC:

1667

ExAC

AF:

0.374

AC:

8364

Asia WGS

AF:

0.363

AC:

1265

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Ser692Pro in exon 17 of OTOG: This variant is not expected to have clinical sign ificance because it has been identified in 72.2% (140/194) of Luhya (Kenyan) chr omosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nl m.nih.gov/projects/SNP; dbSNP rs7106548). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

0.050

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.4

DANN

Benign

0.96

DEOGEN2

Benign

0.049

T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.067

T;T

MetaRNN

Benign

0.000014

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.94

L;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.48

N;.

REVEL

Benign

0.017

Sift

Benign

0.46

T;.

Sift4G

Benign

0.32

T;T

Vest4

0.034

ClinPred

0.0017

GERP RS

-4.2

Varity_R

0.080

gMVP

0.40

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