11-17610204-C-T

Variant names:

• chr11-17610204-C-T
• rs2041028
• NM_001292063.2:c.4904C>T

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.4904C>T​(p.Pro1635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,550,170 control chromosomes in the GnomAD database, including 115,879 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15276 hom., cov: 32)
  • Exomes 𝑓: 0.37 (100603 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.102
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.881634E-6).
• BP6: Variant 11-17610204-C-T is Benign according to our data. Variant chr11-17610204-C-T is described in ClinVar as [Benign]. Clinvar id is 226895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.4904C>T	p.Pro1635Leu	missense_variant	Exon 36 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.4940C>T	p.Pro1647Leu	missense_variant	Exon 35 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.4904C>T	p.Pro1635Leu	missense_variant	Exon 36 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.4940C>T	p.Pro1647Leu	missense_variant	Exon 35 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.2242C>T		non_coding_transcript_exon_variant	Exon 12 of 22	2

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65198 AN: 151866 Hom.: 15251 Cov.: 32

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.353 AC: 52585 AN: 149160 AF XY: 0.360

Gnomad AFR exome AF: 0.635

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.212

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.374 AC: 522758 AN: 1398186 Hom.: 100603 Cov.: 63 AF XY: 0.375 AC XY: 258806 AN XY: 689618

African (AFR) AF: 0.631 AC: 19948 AN: 31598

American (AMR) AF: 0.233 AC: 8306 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8511 AN: 25164

East Asian (EAS) AF: 0.194 AC: 6919 AN: 35732

South Asian (SAS) AF: 0.444 AC: 35150 AN: 79226

European-Finnish (FIN) AF: 0.337 AC: 16239 AN: 48190

Middle Eastern (MID) AF: 0.350 AC: 1992 AN: 5698

European-Non Finnish (NFE) AF: 0.375 AC: 404101 AN: 1078882

Other (OTH) AF: 0.372 AC: 21592 AN: 58002

GnomAD4 genome AF: 0.429 AC: 65264 AN: 151984 Hom.: 15276 Cov.: 32 AF XY: 0.426 AC XY: 31631 AN XY: 74288

African (AFR) AF: 0.624 AC: 25872 AN: 41438

American (AMR) AF: 0.314 AC: 4791 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1147 AN: 3472

East Asian (EAS) AF: 0.202 AC: 1045 AN: 5166

South Asian (SAS) AF: 0.460 AC: 2214 AN: 4808

European-Finnish (FIN) AF: 0.333 AC: 3522 AN: 10588

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25344 AN: 67922

Other (OTH) AF: 0.391 AC: 824 AN: 2110

Alfa AF: 0.388 Hom.: 27038

Bravo AF: 0.428

TwinsUK AF: 0.376 AC: 1396

ALSPAC AF: 0.365 AC: 1407

ExAC AF: 0.313 AC: 8096

Asia WGS AF: 0.372 AC: 1294 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro1647Leu in exon 35 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 63.6% (112/176) of Yoruba (Nigerian) chromosomes from a broad population by the 1000 Genomes Project (http://www.ncb i.nlm.nih.gov/projects/SNP; dbSNP rs2041028). -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.0
DANN	Benign	0.13
DEOGEN2	Benign	0.017	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0000089	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N;.
PhyloP100		0.10
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.059
Sift	Benign	0.59	T;D
Sift4G	Benign	0.44	T;T
Vest4		0.076
ClinPred		0.0053	T
GERP RS		4.1
Varity_R		0.025
gMVP		0.20
Mutation Taster		=98/2	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: rs2041028; hg19: chr11-17631751; COSMIC: COSV61129568;