11-17631896-C-T

Variant names:

• chr11-17631896-C-T
• rs568549806
• NM_001292063.2:c.6907C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_001292063.2(OTOG):​c.6907C>T​(p.Arg2303Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,550,218 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2303H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.559
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014726251).
• BP6: Variant 11-17631896-C-T is Benign according to our data. Variant chr11-17631896-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 229099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00106 (162/152342) while in subpopulation AMR AF = 0.00235 (36/15306). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.6907C>T	p.Arg2303Cys	missense	Exon 41 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.6943C>T	p.Arg2315Cys	missense	Exon 40 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.6907C>T	p.Arg2303Cys	missense	Exon 41 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.6943C>T	p.Arg2315Cys	missense	Exon 40 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.4245C>T		non_coding_transcript_exon	Exon 17 of 22

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00115 AC: 171 AN: 148548 AF XY: 0.00115

Gnomad AFR exome AF: 0.000295

Gnomad AMR exome AF: 0.000977

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00110 AC: 1543 AN: 1397876 Hom.: 2 Cov.: 32 AF XY: 0.00111 AC XY: 766 AN XY: 689468

African (AFR) AF: 0.000443 AC: 14 AN: 31598

American (AMR) AF: 0.000868 AC: 31 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.000442 AC: 35 AN: 79232

European-Finnish (FIN) AF: 0.00284 AC: 136 AN: 47812

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5652

European-Non Finnish (NFE) AF: 0.00117 AC: 1260 AN: 1078970

Other (OTH) AF: 0.00110 AC: 64 AN: 57988

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74494

African (AFR) AF: 0.000216 AC: 9 AN: 41580

American (AMR) AF: 0.00235 AC: 36 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000990

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000767 AC: 19

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria.

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Mar 12, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg2315Cys in exon 40 of OTOG: This variant is classified as likely benign bec ause it has been identified in 0.3% (59/19838) of European Finnish chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs568549806). ACMG criteria applied: PP3; BS1

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.56
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Vest4		0.27
MVP		0.72
ClinPred		0.048	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.42
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs568549806; hg19: chr11-17653443; COSMIC: COSV108163031;