NM_001292063.2:c.8241C>T

Variant names:

• chr11-17641897-C-T
• rs10832824
• NM_001292063.2:c.8241C>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.8241C>T​(p.Cys2747Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,548,770 control chromosomes in the GnomAD database, including 85,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9863 hom., cov: 31)
  • Exomes 𝑓: 0.32 (75595 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.761
• Publications: 12 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=-0.49).
• BP6: Variant 11-17641897-C-T is Benign according to our data. Variant chr11-17641897-C-T is described in ClinVar as Benign. ClinVar VariationId is 226917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.761 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.468 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.8241C>T	p.Cys2747Cys	synonymous	Exon 52 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.8277C>T	p.Cys2759Cys	synonymous	Exon 51 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.8241C>T	p.Cys2747Cys	synonymous	Exon 52 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.8277C>T	p.Cys2759Cys	synonymous	Exon 51 of 55	ENSP00000382323.2	Q6ZRI0-1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53292 AN: 151756 Hom.: 9852 Cov.: 31

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.312

GnomAD2 exomes AF: 0.293 AC: 43350 AN: 148110 AF XY: 0.300

Gnomad AFR exome AF: 0.481

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.324 AC: 452835 AN: 1396896 Hom.: 75595 Cov.: 37 AF XY: 0.325 AC XY: 223629 AN XY: 689050

African (AFR) AF: 0.480 AC: 15153 AN: 31572

American (AMR) AF: 0.191 AC: 6802 AN: 35638

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7230 AN: 25130

East Asian (EAS) AF: 0.133 AC: 4755 AN: 35734

South Asian (SAS) AF: 0.343 AC: 27147 AN: 79090

European-Finnish (FIN) AF: 0.298 AC: 14324 AN: 48118

Middle Eastern (MID) AF: 0.256 AC: 1458 AN: 5690

European-Non Finnish (NFE) AF: 0.332 AC: 357735 AN: 1077982

Other (OTH) AF: 0.315 AC: 18231 AN: 57942

GnomAD4 genome AF: 0.351 AC: 53345 AN: 151874 Hom.: 9863 Cov.: 31 AF XY: 0.347 AC XY: 25748 AN XY: 74240

African (AFR) AF: 0.474 AC: 19592 AN: 41364

American (AMR) AF: 0.258 AC: 3939 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 958 AN: 3466

East Asian (EAS) AF: 0.146 AC: 753 AN: 5144

South Asian (SAS) AF: 0.355 AC: 1711 AN: 4816

European-Finnish (FIN) AF: 0.297 AC: 3138 AN: 10554

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22238 AN: 67924

Other (OTH) AF: 0.312 AC: 657 AN: 2108

Alfa AF: 0.333 Hom.: 21747

Bravo AF: 0.347

Asia WGS AF: 0.281 AC: 977 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 18B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.5
DANN	Benign	0.60
PhyloP100		0.76
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs10832824; hg19: chr11-17663444; COSMIC: COSV61129592; COSMIC: COSV61129592;