rs189910531

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001292063.2(OTOG):c.8125G>A(p.Asp2709Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00037 in 1,417,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 6.70

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020392388).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000316 (402/1272990) while in subpopulation MID AF= 0.00276 (14/5080). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4_exome. There are 187 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.8125G>A	p.Asp2709Asn	missense_variant	Exon 51 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.8161G>A	p.Asp2721Asn	missense_variant	Exon 50 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.8125G>A	p.Asp2709Asn	missense_variant	Exon 51 of 56	5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 link	c.8161G>A	p.Asp2721Asn	missense_variant	Exon 50 of 55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.000853

AC:

123

AN:

144264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00160

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00654

Gnomad NFE

AF:

0.000379

Gnomad OTH

AF:

0.00100

GnomAD3 exomes

AF:

0.000273

AC:

AN:

146344

Hom.:

AF XY:

0.000278

AC XY:

AN XY:

79046

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.000529

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000693

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.000934

GnomAD4 exome

AF:

0.000316

AC:

402

AN:

1272990

Hom.:

Cov.:

AF XY:

0.000299

AC XY:

187

AN XY:

626408

show subpopulations

Gnomad4 AFR exome

AF:

0.00197

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.0000487

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000128

Gnomad4 FIN exome

AF:

0.0000286

Gnomad4 NFE exome

AF:

0.000265

Gnomad4 OTH exome

AF:

0.000541

GnomAD4 genome

AF:

0.000852

AC:

123

AN:

144368

Hom.:

Cov.:

AF XY:

0.000986

AC XY:

AN XY:

69950

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00160

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000379

Gnomad4 OTH

AF:

0.000992

Alfa

AF:

0.000588

Hom.:

Bravo

AF:

0.000865

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000946

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Sep 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2721 of the OTOG protein (p.Asp2721Asn). This variant is present in population databases (rs189910531, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. ClinVar contains an entry for this variant (Variation ID: 504840). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 05, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 18B

Uncertain:2

Dec 26, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 24, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jan 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp2721Asn variant in OTOG has not been previously reported in individuals with hearing loss, but has been identified in 1/868 of African chromosomes and 1/272 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs189910531). Although this variant has been seen in t he general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide s trong support for or against an impact to the protein. In summary, the clinical significance of the p.Asp2721Asn variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

0.030

Eigen_PC

Benign

0.018

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

D;.

REVEL

Benign

0.20

Sift

Benign

0.072

T;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.58

MVP

0.15

ClinPred

0.060

GERP RS

3.7

Varity_R

0.26

gMVP

0.86

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