rs1401870617

Variant names:

• chr11-17634950-T-C
• rs1401870617
• NM_001292063.2:c.7585+2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001292063.2(OTOG):​c.7585+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000216 in 1,386,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: OTOG NM_001292063.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.99
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012010981 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-17634950-T-C is Pathogenic according to our data. Variant chr11-17634950-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 505310.Status of the report is criteria_provided_single_submitter, 1 stars.

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.7585+2T>C		splice_donor intron	N/A	NP_001278992.1
	OTOG	NM_001277269.2		c.7621+2T>C		splice_donor intron	N/A	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.7585+2T>C		splice_donor intron	N/A	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.7621+2T>C		splice_donor intron	N/A	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.4606-660T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000749 AC: 1 AN: 133458 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000160 AC: 2 AN: 1253050 Hom.: 0 Cov.: 35 AF XY: 0.00000161 AC XY: 1 AN XY: 621156

African (AFR) AF: 0.0000701 AC: 2 AN: 28532

American (AMR) AF: 0.00 AC: 0 AN: 33580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22304

East Asian (EAS) AF: 0.00 AC: 0 AN: 29312

South Asian (SAS) AF: 0.00 AC: 0 AN: 76730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4512

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 965852

Other (OTH) AF: 0.00 AC: 0 AN: 50812

GnomAD4 genome AF: 0.00000749 AC: 1 AN: 133458 Hom.: 0 Cov.: 31 AF XY: 0.0000155 AC XY: 1 AN XY: 64350

African (AFR) AF: 0.0000279 AC: 1 AN: 35870

American (AMR) AF: 0.00 AC: 0 AN: 13282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3274

East Asian (EAS) AF: 0.00 AC: 0 AN: 4186

South Asian (SAS) AF: 0.00 AC: 0 AN: 3880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62338

Other (OTH) AF: 0.00 AC: 0 AN: 1848

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.0
GERP RS		5.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1401870617; hg19: chr11-17656497;