11-17629271-G-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001292063.2(OTOG):​c.6667G>A​(p.Val2223Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,550,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V2223V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.248

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.019629031).
BP6
Variant 11-17629271-G-A is Benign according to our data. Variant chr11-17629271-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 227790. Variant chr11-17629271-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 227790. Variant chr11-17629271-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 227790. Variant chr11-17629271-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 227790.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTOGNM_001292063.2 linkc.6667G>A p.Val2223Met missense_variant Exon 40 of 56 ENST00000399397.6 NP_001278992.1 H9KVB3
OTOGNM_001277269.2 linkc.6703G>A p.Val2235Met missense_variant Exon 39 of 55 NP_001264198.1 Q6ZRI0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTOGENST00000399397.6 linkc.6667G>A p.Val2223Met missense_variant Exon 40 of 56 5 NM_001292063.2 ENSP00000382329.2 H9KVB3
OTOGENST00000399391.7 linkc.6703G>A p.Val2235Met missense_variant Exon 39 of 55 5 ENSP00000382323.2 Q6ZRI0-1
OTOGENST00000342528.2 linkn.4005G>A non_coding_transcript_exon_variant Exon 16 of 22 2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152242
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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
GnomAD2 exomes
AF:
0.000357
AC:
53
AN:
148440
AF XY:
0.000275
show subpopulations
Gnomad AFR exome
AF:
0.000444
Gnomad AMR exome
AF:
0.00191
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000365
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000622
AC:
87
AN:
1398220
Hom.:
0
Cov.:
31
AF XY:
0.0000493
AC XY:
34
AN XY:
689628
show subpopulations
African (AFR)
AF:
0.000190
AC:
6
AN:
31596
American (AMR)
AF:
0.00162
AC:
58
AN:
35704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25180
East Asian (EAS)
AF:
0.0000560
AC:
2
AN:
35738
South Asian (SAS)
AF:
0.0000252
AC:
2
AN:
79234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48138
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5682
European-Non Finnish (NFE)
AF:
0.0000167
AC:
18
AN:
1078960
Other (OTH)
AF:
0.0000172
AC:
1
AN:
57988
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
5
11
16
22
27
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000656
AC:
10
AN:
152360
Hom.:
0
Cov.:
33
AF XY:
0.0000805
AC XY:
6
AN XY:
74504
show subpopulations
African (AFR)
AF:
0.000168
AC:
7
AN:
41586
American (AMR)
AF:
0.000196
AC:
3
AN:
15306
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000283
Hom.:
0
Bravo
AF:
0.000162
ExAC
AF:
0.0000463
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Dec 08, 2016
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 227790). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. This variant is present in population databases (rs572886375, gnomAD 0.2%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2235 of the OTOG protein (p.Val2235Met). -

not specified Benign:1
Feb 02, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Val2235Met in exon 39 of OTOG: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 5 mammals (orangutan, rhesus, crab-eating macaque, baboon and green monkey ) have a methionine (Met) at this position despite high nearby amino acid conser vation. In addition, computational prediction tools do not suggest a high likeli hood of impact to the protein. -

OTOG-related disorder Benign:1
Jul 17, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
14
DANN
Benign
0.91
DEOGEN2
Benign
0.037
T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.65
T;T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.020
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N;.
PhyloP100
0.25
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.1
N;.
REVEL
Benign
0.098
Sift
Benign
0.10
T;.
Sift4G
Benign
0.16
T;T
Vest4
0.17
MutPred
0.61
Loss of catalytic residue at V2235 (P = 0.0281);.;
MVP
0.17
ClinPred
0.017
T
GERP RS
-0.18
Varity_R
0.039
gMVP
0.31
Mutation Taster
=92/8
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs572886375; hg19: chr11-17650818; API