rs191722806

chr11-17632199-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):c.7045A>G(p.Ile2349Val) variant causes a missense change. The variant allele was found at a frequency of 0.000772 in 1,551,014 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.55

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007129252).
• BP6: Variant 11-17632199-A-G is Benign according to our data. Variant chr11-17632199-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 450472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00421 (642/152328) while in subpopulation AFR AF= 0.0149 (618/41574). AF 95% confidence interval is 0.0139. There are 3 homozygotes in gnomad4. There are 308 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7045A>G	p.Ile2349Val	missense_variant	42/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7081A>G	p.Ile2361Val	missense_variant	41/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7045A>G	p.Ile2349Val	missense_variant	42/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7081A>G	p.Ile2361Val	missense_variant	41/55	5		A2
OTOG	ENST00000342528.2	n.4383A>G		non_coding_transcript_exon_variant	18/22	2

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 640 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000892 AC: 136 AN: 152398 Hom.: 1 AF XY: 0.000591 AC XY: 48 AN XY: 81252

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000887

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000683

GnomAD4 exome AF: 0.000397 AC: 555 AN: 1398686 Hom.: 3 Cov.: 32 AF XY: 0.000345 AC XY: 238 AN XY: 689844

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.000644

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.000862

GnomAD4 genome AF: 0.00421 AC: 642 AN: 152328 Hom.: 3 Cov.: 32 AF XY: 0.00414 AC XY: 308 AN XY: 74484

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00450

ExAC AF: 0.00164 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 13, 2016

p.Ile2361Val in exon 41 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 2.1% (28/1338) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs191722806). -

OTOG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.82	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.83	N;.
REVEL	Benign	0.22
Sift	Benign	0.085	T;.
Sift4G	Uncertain	0.057	T;T
Vest4		0.31
MVP		0.27
ClinPred		0.026	T
GERP RS		3.5
Varity_R		0.082
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs191722806; hg19: chr11-17653746;