Genetic Variant OTOGL:p.Asn2246Ile (chr12-80372020-A-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_001378609.3(OTOGL):c.6737A>T(p.Asn2246Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. N2246S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OTOGL
NM_001378609.3 missense, splice_region

Scores

Splicing: ADA: 0.01444

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.50

Publications

25 publications found

Variant links:

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 84B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

OTOGL 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3 link	c.6737A>T	p.Asn2246Ile	missense_variant, splice_region_variant	Exon 57 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7 link	c.6737A>T	p.Asn2246Ile	missense_variant, splice_region_variant	Exon 57 of 59	5	NM_001378609.3	ENSP00000447211.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1392374

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692724

African (AFR)

AF:

0.00

AC:

AN:

31300

American (AMR)

AF:

0.00

AC:

AN:

37740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25072

East Asian (EAS)

AF:

0.00

AC:

AN:

36216

South Asian (SAS)

AF:

0.00

AC:

AN:

76960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072066

Other (OTH)

AF:

0.00

AC:

AN:

57608

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.71

T;.;T

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.49

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

4.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.7

.;.;D

REVEL

Benign

0.17

Sift

Benign

0.70

.;.;T

Sift4G

Benign

0.71

.;.;T

Vest4

0.50

MVP

0.32

MPC

0.20

ClinPred

0.95

GERP RS

6.0

gMVP

0.63

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.014

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.010

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