rs4756902

Variant names:

• chr11-17576644-G-A
• rs4756902
• NM_001292063.2:c.2561+14G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277269.2(OTOG):​c.2597+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,535,456 control chromosomes in the GnomAD database, including 113,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10451 hom., cov: 32)
  • Exomes 𝑓: 0.38 (103338 hom.)
• Consequence: OTOG NM_001277269.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.408
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-17576644-G-A is Benign according to our data. Variant chr11-17576644-G-A is described in ClinVar as Benign. ClinVar VariationId is 226871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277269.2. 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.2561+14G>A		intron	N/A	NP_001278992.1
	OTOG	NM_001277269.2		c.2597+14G>A		intron	N/A	NP_001264198.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.2561+14G>A		intron	N/A	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.2597+14G>A		intron	N/A	ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55806 AN: 151632 Hom.: 10443 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.443

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.353

GnomAD2 exomes AF: 0.337 AC: 50288 AN: 149178 AF XY: 0.342

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.373

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.383 AC: 529857 AN: 1383706 Hom.: 103338 Cov.: 31 AF XY: 0.382 AC XY: 260795 AN XY: 683272

African (AFR) AF: 0.372 AC: 11652 AN: 31322

American (AMR) AF: 0.206 AC: 7338 AN: 35680

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 9614 AN: 25098

East Asian (EAS) AF: 0.248 AC: 8855 AN: 35654

South Asian (SAS) AF: 0.316 AC: 25005 AN: 79012

European-Finnish (FIN) AF: 0.374 AC: 18013 AN: 48154

Middle Eastern (MID) AF: 0.350 AC: 1980 AN: 5660

European-Non Finnish (NFE) AF: 0.400 AC: 425824 AN: 1065606

Other (OTH) AF: 0.375 AC: 21576 AN: 57520

GnomAD4 genome AF: 0.368 AC: 55840 AN: 151750 Hom.: 10451 Cov.: 32 AF XY: 0.364 AC XY: 26988 AN XY: 74158

African (AFR) AF: 0.377 AC: 15597 AN: 41418

American (AMR) AF: 0.262 AC: 4004 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1321 AN: 3468

East Asian (EAS) AF: 0.276 AC: 1421 AN: 5152

South Asian (SAS) AF: 0.307 AC: 1477 AN: 4806

European-Finnish (FIN) AF: 0.373 AC: 3925 AN: 10532

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.396 AC: 26852 AN: 67804

Other (OTH) AF: 0.349 AC: 735 AN: 2106

Alfa AF: 0.378 Hom.: 2231

Bravo AF: 0.360

Asia WGS AF: 0.308 AC: 1073 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 18B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.47
PhyloP100		0.41
Mutation Taster		=100/0	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: rs4756902; hg19: chr11-17598191; COSMIC: COSV61128339; COSMIC: COSV61128339;