rs188527711

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001292063.2(OTOG):c.6179G>A(p.Arg2060His) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,549,366 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2060L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.92

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 18B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018020421).

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.6179G>A	p.Arg2060His	missense	Exon 37 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.6215G>A	p.Arg2072His	missense	Exon 36 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OTOG	ENST00000399397.6	TSL:5 MANE Select	c.6179G>A	p.Arg2060His	missense	Exon 37 of 56	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7	TSL:5	c.6215G>A	p.Arg2072His	missense	Exon 36 of 55	ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000342528.2	TSL:2	n.3517G>A		non_coding_transcript_exon	Exon 13 of 22

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000798

AC:

118

AN:

147896

AF XY:

0.000752

show subpopulations

Gnomad AFR exome

AF:

0.000147

Gnomad AMR exome

AF:

0.000692

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000371

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.000697

GnomAD4 exome

AF:

0.00115

AC:

1607

AN:

1397102

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

804

AN XY:

689148

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31598

American (AMR)

AF:

0.00106

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25176

East Asian (EAS)

AF:

0.000168

AC:

AN:

35738

South Asian (SAS)

AF:

0.000202

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.0000638

AC:

AN:

46998

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00136

AC:

1470

AN:

1078962

Other (OTH)

AF:

0.00107

AC:

AN:

57996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

182

272

363

454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000801

AC:

122

AN:

152264

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41548

American (AMR)

AF:

0.000719

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

68010

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000880

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000379

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 18B (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.021

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.7

PhyloP100

3.9

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.039

Sift4G

Benign

0.072

Vest4

0.33

MVP

0.27

ClinPred

0.043

GERP RS

4.5

Varity_R

0.065

gMVP

0.44

Mutation Taster

=90/10

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over