rs7114549

Positions:

• chr11-17632216-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):​c.7062T>C​(p.Ser2354=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,550,302 control chromosomes in the GnomAD database, including 927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (296 hom., cov: 32)
  • Exomes 𝑓: 0.010 (631 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.92

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-17632216-T-C is Benign according to our data. Variant chr11-17632216-T-C is described in ClinVar as [Benign]. Clinvar id is 226905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7062T>C	p.Ser2354=	synonymous_variant	42/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7098T>C	p.Ser2366=	synonymous_variant	41/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7062T>C	p.Ser2354=	synonymous_variant	42/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7098T>C	p.Ser2366=	synonymous_variant	41/55	5		A2
OTOG	ENST00000342528.2	n.4400T>C		non_coding_transcript_exon_variant	18/22	2

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5596 AN: 152170 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0219 AC: 3328 AN: 151620 Hom.: 134 AF XY: 0.0254 AC XY: 2056 AN XY: 80982

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00611

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00601

Gnomad SAS exome AF: 0.0894

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00985

GnomAD4 exome AF: 0.0103 AC: 14382 AN: 1398014 Hom.: 631 Cov.: 32 AF XY: 0.0123 AC XY: 8453 AN XY: 689386

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00661

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.0874

Gnomad4 FIN exome AF: 0.00194

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0368 AC: 5608 AN: 152288 Hom.: 296 Cov.: 32 AF XY: 0.0373 AC XY: 2778 AN XY: 74448

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0106 Hom.: 36

Bravo AF: 0.0376

Asia WGS AF: 0.0640 AC: 220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ser2366Ser in exon 41 of OTOG: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 9.8% (19/194) of Lu hya (Kenyan) chromosomes from a broad population by the 1000 Genomes Project (ht tp://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs7114549). -

OTOG-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2019

This variant is classified as 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.55
DANN	Benign	0.56

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

LitVar

Other links and lift over

dbSNP: rs7114549; hg19: chr11-17653763;