rs61910692

chr11-17586486-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):c.2772C>T(p.His924=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,430,352 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (35 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.89

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=-0.55).
• BP6: Variant 11-17586486-C-T is Benign according to our data. Variant chr11-17586486-C-T is described in ClinVar as [Benign]. Clinvar id is 226876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2111/152268) while in subpopulation AFR AF= 0.0447 (1856/41538). AF 95% confidence interval is 0.043. There are 50 homozygotes in gnomad4. There are 1027 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.2772C>T	p.His924=	synonymous_variant	24/56	ENST00000399397.6
OTOG	NM_001277269.2	c.2808C>T	p.His936=	synonymous_variant	23/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.2772C>T	p.His924=	synonymous_variant	24/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.2808C>T	p.His936=	synonymous_variant	23/55	5		A2
OTOG	ENST00000342528.2	n.276C>T		non_coding_transcript_exon_variant	2/22	2

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2103 AN: 152150 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00274 AC: 203 AN: 74186 Hom.: 4 AF XY: 0.00226 AC XY: 90 AN XY: 39810

Gnomad AFR exome AF: 0.0412

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.000868

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00220 AC: 2815 AN: 1278084 Hom.: 35 Cov.: 29 AF XY: 0.00212 AC XY: 1325 AN XY: 625806

Gnomad4 AFR exome AF: 0.0440

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00259

Gnomad4 FIN exome AF: 0.0000219

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00430

GnomAD4 genome AF: 0.0139 AC: 2111 AN: 152268 Hom.: 50 Cov.: 33 AF XY: 0.0138 AC XY: 1027 AN XY: 74458

Gnomad4 AFR AF: 0.0447

Gnomad4 AMR AF: 0.00666

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00750 Hom.: 5

Bravo AF: 0.0158

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	His936His in exon 23 of OTOG: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 8.2% (10/122) of Afr ican American chromosomes from a broad population by the 1000 Genomes Project (h ttp://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs61910692). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.19
Dann	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs61910692; hg19: chr11-17608033;