NM_001292063.2:c.2486+7G>A

Variant names:

• chr11-17574919-G-A
• rs774905533
• NM_001292063.2:c.2486+7G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001292063.2(OTOG):​c.2486+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,487,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Scores: Splicing: ADA: 0.0001323
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.131
• 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-17574919-G-A is Benign according to our data. Variant chr11-17574919-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 227769.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.2486+7G>A		splice_region_variant, intron_variant	Intron 20 of 55	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.2522+7G>A		splice_region_variant, intron_variant	Intron 19 of 54		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.2486+7G>A		splice_region_variant, intron_variant	Intron 20 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.2522+7G>A		splice_region_variant, intron_variant	Intron 19 of 54	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

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

GnomAD2 exomes AF: 0.0000102 AC: 1 AN: 98320 AF XY: 0.00

Gnomad AFR exome AF: 0.000174

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000300 AC: 4 AN: 1335228 Hom.: 0 Cov.: 32 AF XY: 0.00000461 AC XY: 3 AN XY: 650630

African (AFR) AF: 0.000133 AC: 4 AN: 30050

American (AMR) AF: 0.00 AC: 0 AN: 30398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21108

East Asian (EAS) AF: 0.00 AC: 0 AN: 34134

South Asian (SAS) AF: 0.00 AC: 0 AN: 69360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5376

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1045082

Other (OTH) AF: 0.00 AC: 0 AN: 55322

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74494

African (AFR) AF: 0.000289 AC: 12 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000793

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2522+7G>A in intron 19 of OTOG: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 0.1% (1/718) of African chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs774905533). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.6
DANN	Benign	0.53
PhyloP100		-0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs774905533; hg19: chr11-17596466;