rs570688276

Variant names:

• chr11-17557301-G-A
• rs570688276
• NM_001292063.2:c.843G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17557301-G-A
• chr11-17557301-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):​c.843G>A​(p.Lys281Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,550,602 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (23 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.834
• 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), 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 11-17557301-G-A is Benign according to our data. Variant chr11-17557301-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.834 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (464/152274) while in subpopulation NFE AF = 0.00437 (297/68030). AF 95% confidence interval is 0.00396. There are 1 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 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.843G>A	p.Lys281Lys	synonymous	Exon 8 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.879G>A	p.Lys293Lys	synonymous	Exon 7 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.843G>A	p.Lys281Lys	synonymous	Exon 8 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.879G>A	p.Lys293Lys	synonymous	Exon 7 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000485669.1	TSL:4	n.382G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 464 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00379 AC: 564 AN: 148680 AF XY: 0.00376

Gnomad AFR exome AF: 0.000591

Gnomad AMR exome AF: 0.000977

Gnomad ASJ exome AF: 0.00454

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00895

Gnomad NFE exome AF: 0.00511

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.00435 AC: 6083 AN: 1398328 Hom.: 23 Cov.: 32 AF XY: 0.00434 AC XY: 2993 AN XY: 689686

African (AFR) AF: 0.000348 AC: 11 AN: 31598

American (AMR) AF: 0.00129 AC: 46 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 106 AN: 25182

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

South Asian (SAS) AF: 0.00256 AC: 203 AN: 79234

European-Finnish (FIN) AF: 0.00859 AC: 414 AN: 48190

Middle Eastern (MID) AF: 0.00684 AC: 39 AN: 5698

European-Non Finnish (NFE) AF: 0.00470 AC: 5068 AN: 1078982

Other (OTH) AF: 0.00338 AC: 196 AN: 58002

GnomAD4 genome AF: 0.00305 AC: 464 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74468

African (AFR) AF: 0.000770 AC: 32 AN: 41544

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00437 AC: 297 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00383 Hom.: 0

Bravo AF: 0.00258

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.7
DANN	Benign	0.71
PhyloP100		0.83
Mutation Taster		=99/1	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: rs570688276; hg19: chr11-17578848;