11-17586486-C-T

Variant names:

• chr11-17586486-C-T
• rs61910692
• NM_001292063.2:c.2772C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):​c.2772C>T​(p.His924His) 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:4
• Conservation: PhyloP100: -2.89
• Publications: 0 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=-0.55).
• BP6: Variant 11-17586486-C-T is Benign according to our data. Variant chr11-17586486-C-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

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.2772C>T	p.His924His	synonymous	Exon 24 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.2808C>T	p.His936His	synonymous	Exon 23 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.2772C>T	p.His924His	synonymous	Exon 24 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.2808C>T	p.His936His	synonymous	Exon 23 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.276C>T		non_coding_transcript_exon	Exon 2 of 22

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

GnomAD2 exomes AF: 0.00274 AC: 203 AN: 74186 AF XY: 0.00226

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 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

African (AFR) AF: 0.0440 AC: 1164 AN: 26476

American (AMR) AF: 0.00396 AC: 83 AN: 20954

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 22 AN: 20612

East Asian (EAS) AF: 0.00 AC: 0 AN: 29046

South Asian (SAS) AF: 0.00259 AC: 151 AN: 58382

European-Finnish (FIN) AF: 0.0000219 AC: 1 AN: 45610

Middle Eastern (MID) AF: 0.00907 AC: 48 AN: 5292

European-Non Finnish (NFE) AF: 0.00110 AC: 1120 AN: 1019094

Other (OTH) AF: 0.00430 AC: 226 AN: 52618

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

African (AFR) AF: 0.0447 AC: 1856 AN: 41538

American (AMR) AF: 0.00666 AC: 102 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68034

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00752 Hom.: 10

Bravo AF: 0.0158

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.19
DANN	Benign	0.35
PhyloP100		-2.9
Mutation Taster		=297/3	polymorphism

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

Other links and lift over

dbSNP: rs61910692; hg19: chr11-17608033;