rs182000850

Variant names:

• chr11-17612653-T-C
• rs182000850
• NM_001292063.2:c.6326T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-17612653-T-C
• chr11-17612653-T-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.6326T>C​(p.Val2109Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0029 in 1,550,626 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (103 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.42
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007984966).
• BP6: Variant 11-17612653-T-C is Benign according to our data. Variant chr11-17612653-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00569 (867/152258) while in subpopulation EAS AF = 0.0027 (14/5184). AF 95% confidence interval is 0.00163. There are 26 homozygotes in GnomAd4. There are 639 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.6326T>C	p.Val2109Ala	missense	Exon 38 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.6362T>C	p.Val2121Ala	missense	Exon 37 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.6326T>C	p.Val2109Ala	missense	Exon 38 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.6362T>C	p.Val2121Ala	missense	Exon 37 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.3664T>C		non_coding_transcript_exon	Exon 14 of 22

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 867 AN: 152140 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0676

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00790 AC: 1178 AN: 149190 AF XY: 0.00691

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.000836

Gnomad EAS exome AF: 0.00139

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.000872

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00260 AC: 3637 AN: 1398368 Hom.: 103 Cov.: 31 AF XY: 0.00252 AC XY: 1735 AN XY: 689712

African (AFR) AF: 0.0000949 AC: 3 AN: 31598

American (AMR) AF: 0.000168 AC: 6 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 31 AN: 25178

East Asian (EAS) AF: 0.00140 AC: 50 AN: 35736

South Asian (SAS) AF: 0.000404 AC: 32 AN: 79232

European-Finnish (FIN) AF: 0.0586 AC: 2827 AN: 48218

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.000528 AC: 570 AN: 1078978

Other (OTH) AF: 0.00202 AC: 117 AN: 58028

GnomAD4 genome AF: 0.00569 AC: 867 AN: 152258 Hom.: 26 Cov.: 32 AF XY: 0.00858 AC XY: 639 AN XY: 74450

African (AFR) AF: 0.000385 AC: 16 AN: 41556

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5184

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0676 AC: 717 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68000

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00623 AC: 159

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

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
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.16
Sift	Benign	0.093	T
Sift4G	Uncertain	0.0020	D
Vest4		0.61
MVP		0.29
ClinPred		0.052	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.63
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs182000850; hg19: chr11-17634200; COSMIC: COSV61129213;