rs866627770

Variant names:

• chr11-17633754-G-A
• rs866627770
• NM_001292063.2:c.7147G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001292063.2(OTOG):​c.7147G>A​(p.Gly2383Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,212 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• 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), 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31614083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7147G>A	p.Gly2383Arg	missense_variant	Exon 43 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7183G>A	p.Gly2395Arg	missense_variant	Exon 42 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7147G>A	p.Gly2383Arg	missense_variant	Exon 43 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.7183G>A	p.Gly2395Arg	missense_variant	Exon 42 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.4485G>A		non_coding_transcript_exon_variant	Exon 19 of 22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398212 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 689640

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

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

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078930

Other (OTH) AF: 0.00 AC: 0 AN: 57992

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly2395Arg variant in OTOG has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to asses s the frequency of this variant in the general population. Computational predict ion tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogeni city. In summary, the clinical significance of the p.Gly2395Arg variant is uncer tain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	0.073
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.
PhyloP100		2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	1.2	N;D
REVEL	Uncertain	0.35
Sift	Benign	0.87	T;T
Sift4G	Benign	0.22	T;T
Vest4		0.28
MutPred		0.71		Loss of glycosylation at K2390 (P = 0.1331);.;
MVP		0.65
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.080
gMVP		0.63
Mutation Taster		=77/23	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: rs866627770; hg19: chr11-17655301;