11-17547422-C-T

Variant names:

• chr11-17547422-C-T
• rs2133989074
• NM_001292063.2:c.50C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001292063.2(OTOG):​c.50C>T​(p.Pro17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,259,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.912

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11256093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.50C>T	p.Pro17Leu	missense_variant	Exon 1 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.50C>T	p.Pro17Leu	missense_variant	Exon 1 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.50C>T	p.Pro17Leu	missense_variant	Exon 1 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.50C>T	p.Pro17Leu	missense_variant	Exon 1 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000159 AC: 2 AN: 1259546 Hom.: 0 Cov.: 31 AF XY: 0.00000162 AC XY: 1 AN XY: 616398

African (AFR) AF: 0.00 AC: 0 AN: 25702

American (AMR) AF: 0.0000491 AC: 1 AN: 20372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19692

East Asian (EAS) AF: 0.0000344 AC: 1 AN: 29102

South Asian (SAS) AF: 0.00 AC: 0 AN: 59656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4888

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1019120

Other (OTH) AF: 0.00 AC: 0 AN: 51834

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1911461). This variant has not been reported in the literature in individuals affected with OTOG-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 17 of the OTOG protein (p.Pro17Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		0.91
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.046
Sift	Benign	0.043	D;.
Sift4G	Benign	0.27	T;T
Vest4		0.065
MutPred		0.33		Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);
MVP		0.42
ClinPred		0.14	T
GERP RS		1.3
PromoterAI		-0.00090	Neutral
Varity_R		0.038
gMVP		0.13
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs2133989074; hg19: chr11-17568969; COSMIC: COSV107202969; COSMIC: COSV107202969;