chr11-17645592-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001292063.2(OTOG):​c.8490G>C​(p.Lys2830Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,550,656 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 32 hom., cov: 33)
Exomes 𝑓: 0.019 ( 296 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

2
7
9

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.82

Publications

7 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]
LINC02729 (HGNC:54246): (long intergenic non-protein coding RNA 2729)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0055775344).
BP6
Variant 11-17645592-G-C is Benign according to our data. Variant chr11-17645592-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0156 (2381/152358) while in subpopulation NFE AF = 0.0234 (1591/68022). AF 95% confidence interval is 0.0224. There are 32 homozygotes in GnomAd4. There are 1135 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTOGNM_001292063.2 linkc.8490G>C p.Lys2830Asn missense_variant Exon 55 of 56 ENST00000399397.6 NP_001278992.1 H9KVB3
OTOGNM_001277269.2 linkc.8526G>C p.Lys2842Asn missense_variant Exon 54 of 55 NP_001264198.1 Q6ZRI0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTOGENST00000399397.6 linkc.8490G>C p.Lys2830Asn missense_variant Exon 55 of 56 5 NM_001292063.2 ENSP00000382329.2 H9KVB3
OTOGENST00000399391.7 linkc.8526G>C p.Lys2842Asn missense_variant Exon 54 of 55 5 ENSP00000382323.2 Q6ZRI0-1
LINC02729ENST00000849122.1 linkn.196-519C>G intron_variant Intron 2 of 2

Frequencies

GnomAD3 genomes
AF:
0.0156
AC:
2382
AN:
152240
Hom.:
32
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00417
Gnomad AMI
AF:
0.0713
Gnomad AMR
AF:
0.0115
Gnomad ASJ
AF:
0.0179
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.0258
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0234
Gnomad OTH
AF:
0.0158
GnomAD2 exomes
AF:
0.0149
AC:
2218
AN:
149002
AF XY:
0.0142
show subpopulations
Gnomad AFR exome
AF:
0.00252
Gnomad AMR exome
AF:
0.00940
Gnomad ASJ exome
AF:
0.0147
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0276
Gnomad NFE exome
AF:
0.0234
Gnomad OTH exome
AF:
0.0144
GnomAD4 exome
AF:
0.0187
AC:
26133
AN:
1398298
Hom.:
296
Cov.:
31
AF XY:
0.0182
AC XY:
12552
AN XY:
689672
show subpopulations
African (AFR)
AF:
0.00263
AC:
83
AN:
31598
American (AMR)
AF:
0.0104
AC:
371
AN:
35704
Ashkenazi Jewish (ASJ)
AF:
0.0183
AC:
461
AN:
25182
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35738
South Asian (SAS)
AF:
0.00175
AC:
139
AN:
79236
European-Finnish (FIN)
AF:
0.0294
AC:
1418
AN:
48164
Middle Eastern (MID)
AF:
0.00614
AC:
35
AN:
5698
European-Non Finnish (NFE)
AF:
0.0211
AC:
22761
AN:
1078976
Other (OTH)
AF:
0.0149
AC:
865
AN:
58002
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
1539
3079
4618
6158
7697
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
830
1660
2490
3320
4150
<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:
0.0156
AC:
2381
AN:
152358
Hom.:
32
Cov.:
33
AF XY:
0.0152
AC XY:
1135
AN XY:
74508
show subpopulations
African (AFR)
AF:
0.00414
AC:
172
AN:
41588
American (AMR)
AF:
0.0115
AC:
176
AN:
15314
Ashkenazi Jewish (ASJ)
AF:
0.0179
AC:
62
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4830
European-Finnish (FIN)
AF:
0.0258
AC:
274
AN:
10626
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.0234
AC:
1591
AN:
68022
Other (OTH)
AF:
0.0156
AC:
33
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
123
246
369
492
615
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
30
60
90
120
150
<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:
0.0182
Hom.:
15
Bravo
AF:
0.0150
TwinsUK
AF:
0.0251
AC:
93
ALSPAC
AF:
0.0234
AC:
90
ExAC
AF:
0.00794
AC:
181
Asia WGS
AF:
0.00115
AC:
5
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Mar 15, 2019
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 02, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Nov 24, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Lys2842Asn in exon 54 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 3.8% (7/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs61997203). -

Meniere disease Benign:1
Jan 01, 2020
Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:case-control

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;.
Eigen
Benign
-0.0055
Eigen_PC
Benign
0.0050
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
D;D
MetaRNN
Benign
0.0056
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;.
PhyloP100
1.8
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-4.0
D;.
REVEL
Benign
0.11
Sift
Uncertain
0.0020
D;.
Sift4G
Pathogenic
0.0
D;D
Vest4
0.51
MutPred
0.31
Loss of methylation at K2842 (P = 0.0301);.;
ClinPred
0.015
T
GERP RS
1.2
Varity_R
0.65
gMVP
0.56
Mutation Taster
=83/17
polymorphism

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

Other links and lift over

dbSNP: rs61997203; hg19: chr11-17667139; COSMIC: COSV101251713; API