11-17594039-C-G

Variant names:

• chr11-17594039-C-G
• rs12792504
• NM_001292063.2:c.3289-8C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.3289-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,550,578 control chromosomes in the GnomAD database, including 204 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.014 (192 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, intron
• Scores: Splicing: ADA: 0.002160
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.199
• 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: PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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=-0.82).
• BP6: Variant 11-17594039-C-G is Benign according to our data. Variant chr11-17594039-C-G is described in ClinVar as Benign. ClinVar VariationId is 226882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1602/152324) while in subpopulation NFE AF = 0.0185 (1261/68028). AF 95% confidence interval is 0.0177. There are 12 homozygotes in GnomAd4. There are 704 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.3289-8C>G		splice_region intron	N/A	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.3325-8C>G		splice_region intron	N/A	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.3289-8C>G		splice_region intron	N/A	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.3325-8C>G		splice_region intron	N/A	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.654-8C>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1602 AN: 152206 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00861 AC: 1285 AN: 149176 AF XY: 0.00851

Gnomad AFR exome AF: 0.00266

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.0138 AC: 19249 AN: 1398254 Hom.: 192 Cov.: 32 AF XY: 0.0134 AC XY: 9265 AN XY: 689642

African (AFR) AF: 0.00253 AC: 80 AN: 31598

American (AMR) AF: 0.00185 AC: 66 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 32 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00260 AC: 206 AN: 79226

European-Finnish (FIN) AF: 0.0132 AC: 634 AN: 48164

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5696

European-Non Finnish (NFE) AF: 0.0163 AC: 17606 AN: 1078956

Other (OTH) AF: 0.0106 AC: 615 AN: 57994

GnomAD4 genome AF: 0.0105 AC: 1602 AN: 152324 Hom.: 12 Cov.: 32 AF XY: 0.00945 AC XY: 704 AN XY: 74502

African (AFR) AF: 0.00238 AC: 99 AN: 41582

American (AMR) AF: 0.00229 AC: 35 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0185 AC: 1261 AN: 68028

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00713 Hom.: 1

Bravo AF: 0.00913

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.36
PhyloP100		-0.20
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.050
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: rs12792504; hg19: chr11-17615586;