rs182000850

chr11-17612653-T-Cchr11-17612653-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001292063.2(OTOG):c.6326T>C(p.Val2109Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0029 in 1,550,626 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (103 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.42

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007984966).
• BP6: Variant 11-17612653-T-C is Benign according to our data. Variant chr11-17612653-T-C is described in ClinVar as [Benign]. Clinvar id is 504839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17612653-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.6326T>C	p.Val2109Ala	missense_variant	38/56	ENST00000399397.6
OTOG	NM_001277269.2	c.6362T>C	p.Val2121Ala	missense_variant	37/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.6326T>C	p.Val2109Ala	missense_variant	38/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.6362T>C	p.Val2121Ala	missense_variant	37/55	5		A2
OTOG	ENST00000342528.2	n.3664T>C		non_coding_transcript_exon_variant	14/22	2

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 867 AN: 152140 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0676

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00790 AC: 1178 AN: 149190 Hom.: 44 AF XY: 0.00691 AC XY: 555 AN XY: 80290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000836

Gnomad EAS exome AF: 0.00139

Gnomad SAS exome AF: 0.000710

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.000872

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00260 AC: 3637 AN: 1398368 Hom.: 103 Cov.: 31 AF XY: 0.00252 AC XY: 1735 AN XY: 689712

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00140

Gnomad4 SAS exome AF: 0.000404

Gnomad4 FIN exome AF: 0.0586

Gnomad4 NFE exome AF: 0.000528

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00569 AC: 867 AN: 152258 Hom.: 26 Cov.: 32 AF XY: 0.00858 AC XY: 639 AN XY: 74450

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0676

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00623 AC: 159

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 09, 2017

p.Val2121Ala in exon 37 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 6.3% (1268/20104) of Finnish chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs182000850). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Benign	0.16
Sift	Benign	0.093	T;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.61
MVP		0.29
ClinPred		0.052	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.63

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: rs182000850; hg19: chr11-17634200; COSMIC: COSV61129213;