Genetic Variant NM_001292063.2:c.8125G>C (chr11-17641026-G-C) – 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.8125G>C(p.Asp2709His) variant causes a missense change. The variant allele was found at a frequency of 0.000000786 in 1,272,990 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D2709N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.70

Publications

0 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:

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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;

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.8125G>C	p.Asp2709His	missense	Exon 51 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.8161G>C	p.Asp2721His	missense	Exon 50 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.8125G>C	p.Asp2709His	missense	Exon 51 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.8161G>C	p.Asp2721His	missense	Exon 50 of 55	ENSP00000382323.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.86e-7

AC:

AN:

1272990

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

626408

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27912

American (AMR)

AF:

0.00

AC:

AN:

31956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20522

East Asian (EAS)

AF:

0.00

AC:

AN:

24484

South Asian (SAS)

AF:

0.00

AC:

AN:

78058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5080

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1000128

Other (OTH)

AF:

0.0000200

AC:

AN:

49884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.55

Eigen

Benign

0.18

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

2.9

PhyloP100

6.7

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.21

Sift

Uncertain

0.027

Sift4G

Pathogenic

0.0

Vest4

0.55

MutPred

0.55

Gain of catalytic residue at L2720 (P = 0.1949)

MVP

0.22

ClinPred

0.99

GERP RS

3.7

Varity_R

0.39

gMVP

0.88

Mutation Taster

=55/45

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over