chr11-17560719-C-G

Variant names:

• chr11-17560719-C-G
• rs189947237
• NM_001292063.2:c.1353C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001292063.2(OTOG):​c.1353C>G​(p.Phe451Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.282

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.1353C>G	p.Phe451Leu	missense_variant	Exon 13 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.1389C>G	p.Phe463Leu	missense_variant	Exon 12 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.1353C>G	p.Phe451Leu	missense_variant	Exon 13 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.1389C>G	p.Phe463Leu	missense_variant	Exon 12 of 55	5		ENSP00000382323.2
OTOG	ENST00000498332.5	n.1259C>G		non_coding_transcript_exon_variant	Exon 12 of 16	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000670 AC: 1 AN: 149342 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80390

Gnomad AFR exome AF: 0.000147

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 7.15e-7 AC: 1 AN: 1398170 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689624

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.5
DANN	Benign	0.96
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.71	N;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.58	N;.
REVEL	Benign	0.11
Sift	Benign	0.43	T;.
Sift4G	Benign	0.084	T;T
Vest4		0.29
MutPred		0.52		Loss of catalytic residue at F463 (P = 0.1051);.;
MVP		0.067
ClinPred		0.093	T
GERP RS		-5.3
Varity_R		0.040
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -10

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

Publications

LitVar

Other links and lift over

dbSNP: rs189947237; hg19: chr11-17582266;