rs193083374

Variant names:

• chr11-17610535-C-A
• rs193083374
• NM_001292063.2:c.5235C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17610535-C-A
• chr11-17610535-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):​c.5235C>A​(p.Leu1745Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00939 in 1,550,622 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (80 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.575
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 11-17610535-C-A is Benign according to our data. Variant chr11-17610535-C-A is described in ClinVar as Benign. ClinVar VariationId is 226896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.575 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0068 (1036/152256) while in subpopulation NFE AF = 0.0109 (741/68002). AF 95% confidence interval is 0.0102. There are 8 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.5235C>A	p.Leu1745Leu	synonymous	Exon 36 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.5271C>A	p.Leu1757Leu	synonymous	Exon 35 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.5235C>A	p.Leu1745Leu	synonymous	Exon 36 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.5271C>A	p.Leu1757Leu	synonymous	Exon 35 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.2573C>A		non_coding_transcript_exon	Exon 12 of 22

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1037 AN: 152138 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00913

GnomAD2 exomes AF: 0.00601 AC: 894 AN: 148860 AF XY: 0.00607

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00502

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00687

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00812

GnomAD4 exome AF: 0.00967 AC: 13526 AN: 1398366 Hom.: 80 Cov.: 63 AF XY: 0.00956 AC XY: 6596 AN XY: 689708

African (AFR) AF: 0.00139 AC: 44 AN: 31598

American (AMR) AF: 0.00440 AC: 157 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00385 AC: 97 AN: 25178

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

South Asian (SAS) AF: 0.00140 AC: 111 AN: 79224

European-Finnish (FIN) AF: 0.00590 AC: 285 AN: 48278

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5698

European-Non Finnish (NFE) AF: 0.0115 AC: 12389 AN: 1078958

Other (OTH) AF: 0.00762 AC: 442 AN: 57998

GnomAD4 genome AF: 0.00680 AC: 1036 AN: 152256 Hom.: 8 Cov.: 33 AF XY: 0.00648 AC XY: 482 AN XY: 74436

African (AFR) AF: 0.00226 AC: 94 AN: 41552

American (AMR) AF: 0.00412 AC: 63 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

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

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10622

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0109 AC: 741 AN: 68002

Other (OTH) AF: 0.00903 AC: 19 AN: 2104

Alfa AF: 0.00910 Hom.: 6

Bravo AF: 0.00672

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.82
DANN	Benign	0.51
PhyloP100		0.57
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: rs193083374; hg19: chr11-17632082;