NM_001292063.2:c.1840C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001292063.2(OTOG):c.1840C>T(p.Arg614Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000342 in 1,550,702 control chromosomes in the GnomAD database, including 1 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. R614Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.74

Publications

2 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=0.02940765).

BP6

Variant 11-17570275-C-T is Benign according to our data. Variant chr11-17570275-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 417901.

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.1840C>T	p.Arg614Trp	missense	Exon 17 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.1876C>T	p.Arg626Trp	missense	Exon 16 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.1840C>T	p.Arg614Trp	missense	Exon 17 of 56	ENSP00000382329.2	H9KVB3
OTOG	ENST00000399391.7	TSL:5	c.1876C>T	p.Arg626Trp	missense	Exon 16 of 55	ENSP00000382323.2	Q6ZRI0-1
OTOG	ENST00000498332.5	TSL:5	n.1746C>T		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000280

AC:

AN:

150168

AF XY:

0.000273

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000359

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.000348

AC:

486

AN:

1398508

Hom.:

Cov.:

AF XY:

0.000368

AC XY:

254

AN XY:

689762

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31598

American (AMR)

AF:

0.0000840

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00218

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.000382

AC:

412

AN:

1078992

Other (OTH)

AF:

0.000224

AC:

AN:

58052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000296

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000589

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000464

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal recessive nonsyndromic hearing loss 18B (1)

not specified (1)

OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.061

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.3

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.38

Sift

Benign

0.076

Sift4G

Benign

0.21

Vest4

0.22

MVP

0.59

ClinPred

0.15

GERP RS

3.8

Varity_R

0.19

gMVP

0.64

Mutation Taster

=91/9

polymorphism

(source)

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

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