11-17547502-C-G

Variant names:

• chr11-17547502-C-G
• rs1216368455
• NM_001292063.2:c.94+36C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001277269.2(OTOG):​c.130C>G​(p.Arg44Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000856 in 1,167,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R44Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: OTOG NM_001277269.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.514

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06266087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.94+36C>G		intron_variant	Intron 1 of 55	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.130C>G	p.Arg44Gly	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.94+36C>G		intron_variant	Intron 1 of 55	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.130C>G	p.Arg44Gly	missense_variant	Exon 1 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.56e-7 AC: 1 AN: 1167562 Hom.: 0 Cov.: 31 AF XY: 0.00000178 AC XY: 1 AN XY: 561064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23820

American (AMR) AF: 0.00 AC: 0 AN: 12382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15992

East Asian (EAS) AF: 0.00 AC: 0 AN: 27546

South Asian (SAS) AF: 0.00 AC: 0 AN: 42766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4798

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 967194

Other (OTH) AF: 0.0000210 AC: 1 AN: 47718

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 27, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.46
DANN	Benign	0.50
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.51
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.0040
Sift	Benign	0.12	T
Sift4G	Uncertain	0.024	D
Vest4		0.060
MutPred		0.27		Loss of methylation at R44 (P = 0.0204);
MVP		0.17
ClinPred		0.049	T
GERP RS		-5.2
PromoterAI		0.035	Neutral
Varity_R		0.039
gMVP		0.21
Mutation Taster		=99/1	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

Publications

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Other links and lift over

dbSNP: rs1216368455; hg19: chr11-17569049;