rs554657199

chr11-17611306-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001292063.2(OTOG):c.6006G>A(p.Pro2002=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,550,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.32

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 11-17611306-G-A is Benign according to our data. Variant chr11-17611306-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 505280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.6006G>A	p.Pro2002=	synonymous_variant	36/56	ENST00000399397.6
OTOG	NM_001277269.2	c.6042G>A	p.Pro2014=	synonymous_variant	35/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.6006G>A	p.Pro2002=	synonymous_variant	36/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.6042G>A	p.Pro2014=	synonymous_variant	35/55	5		A2
OTOG	ENST00000342528.2	n.3344G>A		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000739 AC: 11 AN: 148942 Hom.: 0 AF XY: 0.0000872 AC XY: 7 AN XY: 80250

Gnomad AFR exome AF: 0.000444

Gnomad AMR exome AF: 0.0000814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.0000596

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000386 AC: 54 AN: 1398242 Hom.: 0 Cov.: 36 AF XY: 0.0000377 AC XY: 26 AN XY: 689636

Gnomad4 AFR exome AF: 0.000316

Gnomad4 AMR exome AF: 0.0000840

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.0000208

Gnomad4 NFE exome AF: 0.0000241

Gnomad4 OTH exome AF: 0.0000690

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74460

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.000185

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 11, 2016

p.Pro2014Pro in exon 35 of OTOG: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in several populatio ns including 2/7592 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs554657199). -

OTOG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.058
Dann	Benign	0.43

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: rs554657199; hg19: chr11-17632853;