Genetic Variant OTOG:p.Gly2444Cys (chr11-17634131-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001292063.2(OTOG):c.7330G>T(p.Gly2444Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2444S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.45

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), 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.7330G>T	p.Gly2444Cys	missense_variant	Exon 44 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2 link	c.7366G>T	p.Gly2456Cys	missense_variant	Exon 43 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
OTOG	ENST00000399397.6 link	c.7330G>T	p.Gly2444Cys	missense_variant	Exon 44 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7 link	c.7366G>T	p.Gly2456Cys	missense_variant	Exon 43 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2 link	n.4605+257G>T		intron_variant	Intron 19 of 21	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1397128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689108

African (AFR)

AF:

0.00

AC:

AN:

31582

American (AMR)

AF:

0.00

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5092

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078948

Other (OTH)

AF:

0.00

AC:

AN:

57908

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

6.5

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.0

D;.

REVEL

Benign

0.21

Sift

Uncertain

0.013

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.53

MutPred

0.44

Loss of disorder (P = 0.143);.;

MVP

0.56

ClinPred

0.99

GERP RS

4.8

Varity_R

0.56

gMVP

0.87

Mutation Taster

=57/43

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over