11-17612217-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_001292063.2(OTOG):c.6179G>T(p.Arg2060Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000818 in 1,549,256 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. R2060H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 2 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B: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), PanelApp Australia, 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044306666).

BP6

Variant 11-17612217-G-T is Benign according to our data. Variant chr11-17612217-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229097.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.6179G>T	p.Arg2060Leu	missense_variant	Exon 37 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.6215G>T	p.Arg2072Leu	missense_variant	Exon 36 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OTOG	ENST00000399397.6 link	c.6179G>T	p.Arg2060Leu	missense_variant	Exon 37 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.6215G>T	p.Arg2072Leu	missense_variant	Exon 36 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2 link	n.3517G>T		non_coding_transcript_exon_variant	Exon 13 of 22	2

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000581

AC:

AN:

147896

AF XY:

0.000652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000407

Gnomad ASJ exome

AF:

0.000597

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000851

AC:

1189

AN:

1397106

Hom.:

Cov.:

AF XY:

0.000834

AC XY:

575

AN XY:

689150

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31598

American (AMR)

AF:

0.000112

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.000516

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000644

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.0000213

AC:

AN:

47000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00102

AC:

1100

AN:

1078964

Other (OTH)

AF:

0.000328

AC:

AN:

57996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.000519

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.0000318

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00208

AC:

ExAC

AF:

0.000421

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2072 of the OTOG protein (p.Arg2072Leu). This variant is present in population databases (rs188527711, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 229097). 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: "Tolerated"; PolyPhen-2: "Probably 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. -

May 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 07, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Arg2072Leu va riant in OTOG has now been identified by our laboratory in 2 Caucasian individua l with hearing loss; however, one of these individuals carried variants in a dif ferent gene that were sufficient to explain their hearing loss. This variant has also been identified in 0.1% (73/66920) of European chromosomes, including 1 ho mozygous individual, by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; rs188527711). Although this variant has been seen in the gene ral population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In summary, while the clinical s ignificance of the p.Arg2072Leu variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BP5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.044

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.

PhyloP100

3.9

PrimateAI

Benign

0.44

PROVEAN

Benign

1.3

N;.

REVEL

Benign

0.11

Sift

Benign

1.0

T;.

Sift4G

Benign

0.71

T;T

Vest4

0.31

MVP

0.43

ClinPred

0.11

GERP RS

4.5

Varity_R

0.11

gMVP

0.47

Mutation Taster

=89/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over