rs2023483

Positions:

• chr11-17642195-G-C
• chr11-17642195-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):​c.8364G>C​(p.Leu2788=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,548,636 control chromosomes in the GnomAD database, including 81,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10263 hom., cov: 33)
  • Exomes 𝑓: 0.31 (71491 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.72

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 11-17642195-G-C is Benign according to our data. Variant chr11-17642195-G-C is described in ClinVar as [Benign]. Clinvar id is 226919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17642195-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.8364G>C	p.Leu2788=	synonymous_variant	53/56	ENST00000399397.6
OTOG	NM_001277269.2	c.8400G>C	p.Leu2800=	synonymous_variant	52/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.8364G>C	p.Leu2788=	synonymous_variant	53/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.8400G>C	p.Leu2800=	synonymous_variant	52/55	5		A2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53536 AN: 151936 Hom.: 10241 Cov.: 33

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.295 AC: 43244 AN: 146758 Hom.: 7109 AF XY: 0.305 AC XY: 24121 AN XY: 79088

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.191

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.314 AC: 437880 AN: 1396582 Hom.: 71491 Cov.: 37 AF XY: 0.316 AC XY: 217337 AN XY: 688682

Gnomad4 AFR exome AF: 0.521

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.353 AC: 53605 AN: 152054 Hom.: 10263 Cov.: 33 AF XY: 0.350 AC XY: 26017 AN XY: 74334

Gnomad4 AFR AF: 0.507

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.320

Alfa AF: 0.314 Hom.: 1466

Bravo AF: 0.348

Asia WGS AF: 0.349 AC: 1215 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Leu2800Leu in exon 52 of OTOG: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 58.8% (114/194) of Luhya (Kenyan) chromosomes from a broad population by the 1000 Genomes Project ( http://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs2023483). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal recessive nonsyndromic hearing loss 18B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0060
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs2023483; hg19: chr11-17663742; COSMIC: COSV61130391; COSMIC: COSV61130391;