rs866627770

Positions:

• chr11-17633754-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7147G>A	p.Gly2383Arg	missense_variant	43/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7183G>A	p.Gly2395Arg	missense_variant	42/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7147G>A	p.Gly2383Arg	missense_variant	43/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7183G>A	p.Gly2395Arg	missense_variant	42/55	5		A2
OTOG	ENST00000342528.2	n.4485G>A		non_coding_transcript_exon_variant	19/22	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 21, 2016

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;.
MutationTaster	Benign	0.92	N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs866627770; hg19: chr11-17655301;