rs16934404

Variant names:

• chr11-17573271-C-T
• rs16934404
• NM_001292063.2:c.2274C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001292063.2(OTOG):​c.2274C>T​(p.Arg758Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,528,074 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (91 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (256 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.15
• Publications: 2 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-17573271-C-T is Benign according to our data. Variant chr11-17573271-C-T is described in ClinVar as Benign. ClinVar VariationId is 226867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0817 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.2274C>T	p.Arg758Arg	synonymous	Exon 19 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.2310C>T	p.Arg770Arg	synonymous	Exon 18 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.2274C>T	p.Arg758Arg	synonymous	Exon 19 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.2310C>T	p.Arg770Arg	synonymous	Exon 18 of 55	ENSP00000382323.2	Q6ZRI0-1

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3296 AN: 152178 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0880

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0176 AC: 2311 AN: 130940 AF XY: 0.0163

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.0293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0861

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00582 AC: 8009 AN: 1375778 Hom.: 256 Cov.: 32 AF XY: 0.00582 AC XY: 3940 AN XY: 677446

African (AFR) AF: 0.0557 AC: 1749 AN: 31394

American (AMR) AF: 0.0288 AC: 1019 AN: 35364

Ashkenazi Jewish (ASJ) AF: 0.0000402 AC: 1 AN: 24904

East Asian (EAS) AF: 0.0877 AC: 3115 AN: 35520

South Asian (SAS) AF: 0.0137 AC: 1081 AN: 78734

European-Finnish (FIN) AF: 0.0000884 AC: 3 AN: 33922

Middle Eastern (MID) AF: 0.00399 AC: 21 AN: 5260

European-Non Finnish (NFE) AF: 0.000464 AC: 498 AN: 1073260

Other (OTH) AF: 0.00909 AC: 522 AN: 57420

GnomAD4 genome AF: 0.0217 AC: 3302 AN: 152296 Hom.: 91 Cov.: 33 AF XY: 0.0226 AC XY: 1686 AN XY: 74466

African (AFR) AF: 0.0554 AC: 2301 AN: 41554

American (AMR) AF: 0.0241 AC: 369 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0884 AC: 458 AN: 5182

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68024

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0112 Hom.: 17

Bravo AF: 0.0266

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.68
DANN	Benign	0.62
PhyloP100		-1.1
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16934404; hg19: chr11-17594818;