rs186893662

Variant names:

• chr11-17553376-G-A
• rs186893662
• NM_001292063.2:c.397G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000399397.6(OTOG):​c.397G>A​(p.Gly133Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,463,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: OTOG ENST00000399397.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 9.52
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03608471).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399397.6. 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.397G>A	p.Gly133Ser	missense	Exon 6 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.433G>A	p.Gly145Ser	missense	Exon 5 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.397G>A	p.Gly133Ser	missense	Exon 6 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.433G>A	p.Gly145Ser	missense	Exon 5 of 55	ENSP00000382323.2
	OTOG	ENST00000428619.1	TSL:3	c.214G>A	p.Gly72Ser	missense	Exon 4 of 4	ENSP00000399057.2

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000579 AC: 48 AN: 82878 AF XY: 0.000527

Gnomad AFR exome AF: 0.000167

Gnomad AMR exome AF: 0.000613

Gnomad ASJ exome AF: 0.00265

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.000960

Gnomad OTH exome AF: 0.000409

GnomAD4 exome AF: 0.000603 AC: 791 AN: 1311072 Hom.: 0 Cov.: 32 AF XY: 0.000594 AC XY: 378 AN XY: 636414

African (AFR) AF: 0.000104 AC: 3 AN: 28786

American (AMR) AF: 0.000485 AC: 11 AN: 22700

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 50 AN: 19456

East Asian (EAS) AF: 0.000201 AC: 7 AN: 34858

South Asian (SAS) AF: 0.00 AC: 0 AN: 64646

European-Finnish (FIN) AF: 0.000244 AC: 11 AN: 45016

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5278

European-Non Finnish (NFE) AF: 0.000654 AC: 678 AN: 1036154

Other (OTH) AF: 0.000554 AC: 30 AN: 54178

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41 AN XY: 74464

African (AFR) AF: 0.000168 AC: 7 AN: 41552

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68018

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

Alfa AF: 0.000852 Hom.: 3

Bravo AF: 0.000582

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000195 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	1	-	Autosomal recessive nonsyndromic hearing loss 18B (1)
-	1	-	Hearing impairment (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.65
MVP		0.22
ClinPred		0.17	T
GERP RS		5.4
Varity_R		0.85
gMVP		0.60
Mutation Taster		=11/89	disease causing

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: rs186893662; hg19: chr11-17574923; COSMIC: COSV101250729; COSMIC: COSV101250729;