11-17634224-G-C

Position:

• chr11-17634224-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_001292063.2(OTOG):​c.7423G>C​(p.Gly2475Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,398,236 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: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.51

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Dann, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.37069154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.7423G>C	p.Gly2475Arg	missense_variant	44/56	ENST00000399397.6
OTOG	NM_001277269.2	c.7459G>C	p.Gly2487Arg	missense_variant	43/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.7423G>C	p.Gly2475Arg	missense_variant	44/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.7459G>C	p.Gly2487Arg	missense_variant	43/55	5		A2
OTOG	ENST00000342528.2	n.4605+350G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000136 AC: 2 AN: 146884 Hom.: 0 AF XY: 0.0000252 AC XY: 2 AN XY: 79218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000186

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1398236 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 689652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000517

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2016

The p.Gly2487Arg variant in OTOG has not been previously in individuals with hea ring loss. Data from large population studies is insufficient to assess the freq uency of this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signific ance of the p.Gly2487Arg variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 504965). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2487 of the OTOG protein (p.Gly2487Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0010	D;T
Vest4		0.54
MutPred		0.52		Gain of disorder (P = 0.0962);.;
MVP		0.49
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.47
gMVP		0.92

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: rs771765463; hg19: chr11-17655771;