NM_001292063.2:c.8690G>C

Variant names:

• chr11-17645892-G-C
• rs11024357
• NM_001292063.2:c.8690G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001292063.2(OTOG):​c.8690G>C​(p.Trp2897Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,550,390 control chromosomes in the GnomAD database, including 39,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3050 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36252 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.16
• Publications: 13 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016483366).
• BP6: Variant 11-17645892-G-C is Benign according to our data. Variant chr11-17645892-G-C is described in ClinVar as Benign. ClinVar VariationId is 226923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.8690G>C	p.Trp2897Ser	missense_variant	Exon 56 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.8726G>C	p.Trp2909Ser	missense_variant	Exon 55 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.8690G>C	p.Trp2897Ser	missense_variant	Exon 56 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.8726G>C	p.Trp2909Ser	missense_variant	Exon 55 of 55	5		ENSP00000382323.2
LINC02729	ENST00000849122.1	n.195+545C>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29999 AN: 152128 Hom.: 3056 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0712

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.200 AC: 29800 AN: 148742 AF XY: 0.210

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.0682

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.224 AC: 313121 AN: 1398144 Hom.: 36252 Cov.: 35 AF XY: 0.226 AC XY: 155598 AN XY: 689584

African (AFR) AF: 0.150 AC: 4753 AN: 31598

American (AMR) AF: 0.120 AC: 4268 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4633 AN: 25182

East Asian (EAS) AF: 0.0899 AC: 3214 AN: 35738

South Asian (SAS) AF: 0.272 AC: 21554 AN: 79236

European-Finnish (FIN) AF: 0.238 AC: 11408 AN: 48018

Middle Eastern (MID) AF: 0.193 AC: 1102 AN: 5698

European-Non Finnish (NFE) AF: 0.232 AC: 250186 AN: 1078972

Other (OTH) AF: 0.207 AC: 12003 AN: 57998

GnomAD4 genome AF: 0.197 AC: 30000 AN: 152246 Hom.: 3050 Cov.: 32 AF XY: 0.197 AC XY: 14667 AN XY: 74432

African (AFR) AF: 0.153 AC: 6376 AN: 41568

American (AMR) AF: 0.160 AC: 2454 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3472

East Asian (EAS) AF: 0.0714 AC: 369 AN: 5168

South Asian (SAS) AF: 0.268 AC: 1293 AN: 4824

European-Finnish (FIN) AF: 0.241 AC: 2550 AN: 10602

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15760 AN: 67994

Other (OTH) AF: 0.187 AC: 395 AN: 2114

Alfa AF: 0.213 Hom.: 1244

Bravo AF: 0.183

TwinsUK AF: 0.225 AC: 834

ALSPAC AF: 0.240 AC: 926

ExAC AF: 0.205 AC: 4346

Asia WGS AF: 0.170 AC: 594 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Trp2909Ser in exon 55 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 32.1% (9/28) of Spanish (Iberian) ch romosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.n lm.nih.gov/projects/SNP; dbSNP rs11024357). -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 18B Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.41	N;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D;.
REVEL	Uncertain	0.31
Sift	Benign	0.29	T;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.27
ClinPred		0.014	T
GERP RS		5.3
Varity_R		0.54
gMVP		0.36
Mutation Taster		=39/61	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11024357; hg19: chr11-17667439; COSMIC: COSV68038598;