11-17645579-G-A

Position:

chr11-17645579-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001292063.2(OTOG):c.8477G>A(p.Arg2826His) variant causes a missense change. The variant allele was found at a frequency of 0.0000987 in 1,550,608 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 0.00050 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 6.73

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026176095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.8477G>A	p.Arg2826His	missense_variant	55/56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 linkuse as main transcript	c.8513G>A	p.Arg2838His	missense_variant	54/55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.8477G>A	p.Arg2826His	missense_variant	55/56	5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 linkuse as main transcript	c.8513G>A	p.Arg2838His	missense_variant	54/55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

AF:

0.000499

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000141

AC:

AN:

148840

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

80188

show subpopulations

Gnomad AFR exome

AF:

0.00193

Gnomad AMR exome

AF:

0.0000815

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000928

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000300

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000551

AC:

AN:

1398266

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

689654

show subpopulations

Gnomad4 AFR exome

AF:

0.00127

Gnomad4 AMR exome

AF:

0.0000840

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000101

Gnomad4 FIN exome

AF:

0.000249

Gnomad4 NFE exome

AF:

0.00000649

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.000499

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000527

Hom.:

Bravo

AF:

0.000540

ExAC

AF:

0.0000435

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 27, 2022	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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1194189). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. This variant is present in population databases (rs544815967, gnomAD 0.2%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2838 of the OTOG protein (p.Arg2838His). -

OTOG-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2024

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

Benign

0.21

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

0.58

N;N

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.7

D;.

REVEL

Benign

0.18

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0040

D;D

Vest4

0.26

MVP

0.20

ClinPred

0.22

GERP RS

4.2

Varity_R

0.19

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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