rs11024350

Variant names:

• chr11-17635139-C-T
• rs11024350
• NM_001292063.2:c.7645C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):​c.7645C>T​(p.Leu2549Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,548,856 control chromosomes in the GnomAD database, including 13,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1165 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12634 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.29
• Publications: 8 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]

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-17635139-C-T is Benign according to our data. Variant chr11-17635139-C-T is described in ClinVar as Benign. ClinVar VariationId is 226911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7645C>T	p.Leu2549Leu	synonymous_variant	Exon 46 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7681C>T	p.Leu2561Leu	synonymous_variant	Exon 45 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7645C>T	p.Leu2549Leu	synonymous_variant	Exon 46 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.7681C>T	p.Leu2561Leu	synonymous_variant	Exon 45 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.4606-471C>T		intron_variant	Intron 19 of 21	2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17885 AN: 151960 Hom.: 1166 Cov.: 32

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.133 AC: 18923 AN: 141776 AF XY: 0.139

Gnomad AFR exome AF: 0.0756

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.250

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.131 AC: 183533 AN: 1396778 Hom.: 12634 Cov.: 34 AF XY: 0.134 AC XY: 91989 AN XY: 688866

African (AFR) AF: 0.0809 AC: 2556 AN: 31588

American (AMR) AF: 0.0709 AC: 2531 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3806 AN: 25158

East Asian (EAS) AF: 0.213 AC: 7621 AN: 35734

South Asian (SAS) AF: 0.174 AC: 13748 AN: 79200

European-Finnish (FIN) AF: 0.118 AC: 5558 AN: 47072

Middle Eastern (MID) AF: 0.129 AC: 736 AN: 5696

European-Non Finnish (NFE) AF: 0.129 AC: 138811 AN: 1078686

Other (OTH) AF: 0.141 AC: 8166 AN: 57960

GnomAD4 genome AF: 0.118 AC: 17883 AN: 152078 Hom.: 1165 Cov.: 32 AF XY: 0.119 AC XY: 8827 AN XY: 74336

African (AFR) AF: 0.0770 AC: 3193 AN: 41480

American (AMR) AF: 0.0929 AC: 1421 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 528 AN: 3472

East Asian (EAS) AF: 0.233 AC: 1199 AN: 5136

South Asian (SAS) AF: 0.183 AC: 879 AN: 4810

European-Finnish (FIN) AF: 0.120 AC: 1277 AN: 10604

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8849 AN: 67970

Other (OTH) AF: 0.126 AC: 266 AN: 2112

Alfa AF: 0.124 Hom.: 1686

Bravo AF: 0.112

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu2561Leu in exon 45 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 18.5% (37/200) of H an Chinese chromosomes from a broad population by the 1000 Genomes Project (http ://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs11024350). -

May 09, 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.1
DANN	Benign	0.66
PhyloP100		1.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11024350; hg19: chr11-17656686; COSMIC: COSV107428908;