NM_001292063.2:c.534C>T

Variant names:

• chr11-17553513-C-T
• rs61995706
• NM_001292063.2:c.534C>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.534C>T​(p.Ser178Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000709 in 1,435,582 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.52
• 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=-0.72).
• BP6: Variant 11-17553513-C-T is Benign according to our data. Variant chr11-17553513-C-T is described in ClinVar as Benign. ClinVar VariationId is 504777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00352 (536/152306) while in subpopulation AFR AF = 0.0125 (518/41562). AF 95% confidence interval is 0.0116. There are 2 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.534C>T	p.Ser178Ser	synonymous	Exon 6 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.570C>T	p.Ser190Ser	synonymous	Exon 5 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.534C>T	p.Ser178Ser	synonymous	Exon 6 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.570C>T	p.Ser190Ser	synonymous	Exon 5 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000498332.5	TSL:5	n.440C>T		non_coding_transcript_exon	Exon 5 of 16

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152188 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00111 AC: 77 AN: 69078 AF XY: 0.000866

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000376 AC: 482 AN: 1283276 Hom.: 4 Cov.: 32 AF XY: 0.000334 AC XY: 207 AN XY: 620378

African (AFR) AF: 0.0149 AC: 417 AN: 28008

American (AMR) AF: 0.000282 AC: 5 AN: 17720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18638

East Asian (EAS) AF: 0.00 AC: 0 AN: 33904

South Asian (SAS) AF: 0.0000685 AC: 4 AN: 58372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44058

Middle Eastern (MID) AF: 0.00213 AC: 11 AN: 5176

European-Non Finnish (NFE) AF: 0.00000488 AC: 5 AN: 1024458

Other (OTH) AF: 0.000756 AC: 40 AN: 52942

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152306 Hom.: 2 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74466

African (AFR) AF: 0.0125 AC: 518 AN: 41562

American (AMR) AF: 0.000653 AC: 10 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00319 Hom.: 2

Bravo AF: 0.00393

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.0
DANN	Benign	0.55
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism

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: rs61995706; hg19: chr11-17575060;