chr11-17547442-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001292063.2(OTOG):​c.70G>A​(p.Glu24Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.546
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.080675215).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OTOGNM_001292063.2 linkuse as main transcriptc.70G>A p.Glu24Lys missense_variant 1/56 ENST00000399397.6
OTOGNM_001277269.2 linkuse as main transcriptc.70G>A p.Glu24Lys missense_variant 1/55

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTOGENST00000399397.6 linkuse as main transcriptc.70G>A p.Glu24Lys missense_variant 1/565 NM_001292063.2 P2
OTOGENST00000399391.7 linkuse as main transcriptc.70G>A p.Glu24Lys missense_variant 1/555 A2Q6ZRI0-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
8.09e-7
AC:
1
AN:
1236122
Hom.:
0
Cov.:
31
AF XY:
0.00000166
AC XY:
1
AN XY:
602886
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.92e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 18, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 24 of the OTOG protein (p.Glu24Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
11
DANN
Uncertain
0.99
DEOGEN2
Benign
0.025
T;.
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.57
T;T
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.081
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.63
N;.
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.24
N;.
REVEL
Benign
0.071
Sift
Benign
0.51
T;.
Sift4G
Pathogenic
0.0
D;D
Vest4
0.13
MutPred
0.37
Gain of MoRF binding (P = 0.0013);Gain of MoRF binding (P = 0.0013);
MVP
0.048
ClinPred
0.078
T
GERP RS
0.80
Varity_R
0.048
gMVP
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1447411019; hg19: chr11-17568989; API