rs7114549

Variant names:

• chr11-17632216-T-C
• rs7114549
• NM_001292063.2:c.7062T>C

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.7062T>C​(p.Ser2354Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,550,302 control chromosomes in the GnomAD database, including 927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (296 hom., cov: 32)
  • Exomes 𝑓: 0.010 (631 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.92
• Publications: 1 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), PanelApp Australia, 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=-0.84).
• BP6: Variant 11-17632216-T-C is Benign according to our data. Variant chr11-17632216-T-C is described in ClinVar as Benign. ClinVar VariationId is 226905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.7062T>C	p.Ser2354Ser	synonymous	Exon 42 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.7098T>C	p.Ser2366Ser	synonymous	Exon 41 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.7062T>C	p.Ser2354Ser	synonymous	Exon 42 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.7098T>C	p.Ser2366Ser	synonymous	Exon 41 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.4400T>C		non_coding_transcript_exon	Exon 18 of 22

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5596 AN: 152170 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0219 AC: 3328 AN: 151620 AF XY: 0.0254

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00611

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00601

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00985

GnomAD4 exome AF: 0.0103 AC: 14382 AN: 1398014 Hom.: 631 Cov.: 32 AF XY: 0.0123 AC XY: 8453 AN XY: 689386

African (AFR) AF: 0.117 AC: 3700 AN: 31586

American (AMR) AF: 0.00661 AC: 236 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 322 AN: 25168

East Asian (EAS) AF: 0.0109 AC: 388 AN: 35724

South Asian (SAS) AF: 0.0874 AC: 6923 AN: 79230

European-Finnish (FIN) AF: 0.00194 AC: 94 AN: 48486

Middle Eastern (MID) AF: 0.0194 AC: 110 AN: 5668

European-Non Finnish (NFE) AF: 0.00156 AC: 1684 AN: 1078490

Other (OTH) AF: 0.0160 AC: 925 AN: 57970

GnomAD4 genome AF: 0.0368 AC: 5608 AN: 152288 Hom.: 296 Cov.: 32 AF XY: 0.0373 AC XY: 2778 AN XY: 74448

African (AFR) AF: 0.110 AC: 4574 AN: 41532

American (AMR) AF: 0.0139 AC: 212 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.0104 AC: 54 AN: 5176

South Asian (SAS) AF: 0.103 AC: 498 AN: 4820

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68038

Other (OTH) AF: 0.0293 AC: 62 AN: 2116

Alfa AF: 0.0115 Hom.: 40

Bravo AF: 0.0376

Asia WGS AF: 0.0640 AC: 220 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.84
CADD	Benign	0.55
DANN	Benign	0.56
PhyloP100		-4.9
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7114549; hg19: chr11-17653763;