rs188456860

Variant names:

• chr11-17639474-G-A
• rs188456860
• NM_001292063.2:c.7935+11G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17639474-G-A
• chr11-17639474-G-T

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.7935+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,550,432 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (56 hom.)
• Consequence: OTOG NM_001292063.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.538
• Publications: 1 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=-0.81).
• BP6: Variant 11-17639474-G-A is Benign according to our data. Variant chr11-17639474-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00144 (219/152230) while in subpopulation SAS AF = 0.0278 (134/4814). AF 95% confidence interval is 0.024. There are 3 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.7935+11G>A		intron	N/A	NP_001278992.1
	OTOG	NM_001277269.2		c.7971+11G>A		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.7935+11G>A		intron	N/A	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.7971+11G>A		intron	N/A	ENSP00000382323.2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152112 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00495 AC: 740 AN: 149634 AF XY: 0.00611

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00788

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000289

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00199 AC: 2779 AN: 1398202 Hom.: 56 Cov.: 30 AF XY: 0.00268 AC XY: 1847 AN XY: 689642

African (AFR) AF: 0.0000633 AC: 2 AN: 31590

American (AMR) AF: 0.00255 AC: 91 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00509 AC: 182 AN: 35738

South Asian (SAS) AF: 0.0261 AC: 2068 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48238

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5700

European-Non Finnish (NFE) AF: 0.000206 AC: 222 AN: 1078800

Other (OTH) AF: 0.00364 AC: 211 AN: 58026

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152230 Hom.: 3 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74424

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.00176 AC: 27 AN: 15304

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

East Asian (EAS) AF: 0.00870 AC: 45 AN: 5174

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68002

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

Alfa AF: 0.000402 Hom.: 0

Bravo AF: 0.00114

Asia WGS AF: 0.0230 AC: 78 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-0.81
CADD	Benign	8.0
DANN	Benign	0.67
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism

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: rs188456860; hg19: chr11-17661021;