rs76461792

Positions:

• chr11-17635125-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001292063.2(OTOG):​c.7631G>A​(p.Arg2544Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0041 in 1,549,308 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (20 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.90

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008668214).
• BP6: Variant 11-17635125-G-A is Benign according to our data. Variant chr11-17635125-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227796.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr11-17635125-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7631G>A	p.Arg2544Gln	missense_variant	46/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7667G>A	p.Arg2556Gln	missense_variant	45/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7631G>A	p.Arg2544Gln	missense_variant	46/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.7667G>A	p.Arg2556Gln	missense_variant	45/55	5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.4606-485G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00276 AC: 391 AN: 141822 Hom.: 4 AF XY: 0.00311 AC XY: 239 AN XY: 76834

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00321

Gnomad FIN exome AF: 0.000831

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.00422 AC: 5890 AN: 1397114 Hom.: 20 Cov.: 33 AF XY: 0.00410 AC XY: 2828 AN XY: 689058

Gnomad4 AFR exome AF: 0.000665

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00337

Gnomad4 FIN exome AF: 0.000739

Gnomad4 NFE exome AF: 0.00488

Gnomad4 OTH exome AF: 0.00347

GnomAD4 genome AF: 0.00308 AC: 468 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74412

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00524

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00408 Hom.: 2

Bravo AF: 0.00330

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ExAC AF: 0.00194 AC: 42

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	OTOG: BP4, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 06, 2017	p.Arg2556Gln in exon 45 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.5% (292/61730) of European chrom osomes, including 1 homozygote, by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs76461792). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2017	- -

Meniere disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.061
Sift	Benign	0.057	T;.
Sift4G	Benign	0.21	T;T
Vest4		0.12
MVP		0.22
ClinPred		0.024	T
GERP RS		5.4
Varity_R		0.19
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs76461792; hg19: chr11-17656672;