rs61995750

Positions:

chr11-17638480-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001292063.2(OTOG):c.7825C>A(p.Gln2609Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,550,110 control chromosomes in the GnomAD database, including 8 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2609L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0045 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.13

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=0.008367062).

BP6

Variant 11-17638480-C-A is Benign according to our data. Variant chr11-17638480-C-A is described in ClinVar as [Benign]. Clinvar id is 227799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17638480-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00454 (691/152338) while in subpopulation AFR AF= 0.0153 (634/41568). AF 95% confidence interval is 0.0143. There are 7 homozygotes in gnomad4. There are 329 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2 linkuse as main transcript	c.7825C>A	p.Gln2609Lys	missense_variant	48/56	ENST00000399397.6
OTOG	NM_001277269.2 linkuse as main transcript	c.7861C>A	p.Gln2621Lys	missense_variant	47/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6 linkuse as main transcript	c.7825C>A	p.Gln2609Lys	missense_variant	48/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7 linkuse as main transcript	c.7861C>A	p.Gln2621Lys	missense_variant	47/55	5		A2	Q6ZRI0-1
OTOG	ENST00000342528.2 linkuse as main transcript	n.4737C>A		non_coding_transcript_exon_variant	21/22	2

Frequencies

GnomAD3 genomes

AF:

0.00454

AC:

691

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.000984

AC:

146

AN:

148366

Hom.:

AF XY:

0.000789

AC XY:

AN XY:

79888

show subpopulations

Gnomad AFR exome

AF:

0.0156

Gnomad AMR exome

AF:

0.000978

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000614

Gnomad NFE exome

AF:

0.000201

Gnomad OTH exome

AF:

0.000929

GnomAD4 exome

AF:

0.000486

AC:

679

AN:

1397772

Hom.:

Cov.:

AF XY:

0.000439

AC XY:

303

AN XY:

689436

show subpopulations

Gnomad4 AFR exome

AF:

0.0143

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.000314

Gnomad4 NFE exome

AF:

0.0000908

Gnomad4 OTH exome

AF:

0.00110

GnomAD4 genome

AF:

0.00454

AC:

691

AN:

152338

Hom.:

Cov.:

AF XY:

0.00442

AC XY:

329

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0153

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00523

ExAC

AF:

0.000673

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2017

p.Gln2621Lys in exon 47 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 1.5% (232/15266) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs61995750). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.025

T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0084

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.090

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.70

N;.

REVEL

Benign

0.060

Sift

Benign

0.31

T;.

Sift4G

Benign

0.83

T;T

Vest4

0.20

MVP

0.10

ClinPred

0.0089

GERP RS

3.4

Varity_R

0.14

gMVP

0.58

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