rs569159135

Variant names:

• chr11-17642129-C-A
• rs569159135
• NM_001292063.2:c.8298C>A
• OTOG p.Pro2766Pro

Your query was ambiguous. Multiple possible variants found:

• chr11-17642129-C-A
• chr11-17642129-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001292063.2(OTOG):​c.8298C>A​(p.Pro2766Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,541,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2766P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: OTOG NM_001292063.2 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.799
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-17642129-C-A is Benign according to our data. Variant chr11-17642129-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 505066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.799 with no splicing effect.

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.8298C>A	p.Pro2766Pro	splice_region synonymous	Exon 53 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.8334C>A	p.Pro2778Pro	splice_region synonymous	Exon 52 of 55	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.8298C>A	p.Pro2766Pro	splice_region synonymous	Exon 53 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.8334C>A	p.Pro2778Pro	splice_region synonymous	Exon 52 of 55	ENSP00000382323.2	Q6ZRI0-1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

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: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000261 AC: 37 AN: 141978 AF XY: 0.000263

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000828

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000676

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000522 AC: 725 AN: 1389248 Hom.: 0 Cov.: 32 AF XY: 0.000482 AC XY: 330 AN XY: 683984

African (AFR) AF: 0.0000637 AC: 2 AN: 31410

American (AMR) AF: 0.0000849 AC: 3 AN: 35338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24636

East Asian (EAS) AF: 0.00 AC: 0 AN: 35632

South Asian (SAS) AF: 0.00 AC: 0 AN: 77648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.000657 AC: 705 AN: 1073584

Other (OTH) AF: 0.000261 AC: 15 AN: 57580

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74464

African (AFR) AF: 0.000385 AC: 16 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.000261

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.018
DANN	Benign	0.24
PhyloP100		-0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs569159135;

hg19: chr11-17663676;