11-17547388-T-C

Variant names:

• chr11-17547388-T-C
• rs773298682
• NM_001292063.2:c.16T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001292063.2(OTOG):​c.16T>C​(p.Ser6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000793 in 1,261,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00600

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0115226805).
• BP6: Variant 11-17547388-T-C is Benign according to our data. Variant chr11-17547388-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 666740.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.16T>C	p.Ser6Pro	missense_variant	Exon 1 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.16T>C	p.Ser6Pro	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.16T>C	p.Ser6Pro	missense_variant	Exon 1 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.16T>C	p.Ser6Pro	missense_variant	Exon 1 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.93e-7 AC: 1 AN: 1261530 Hom.: 0 Cov.: 31 AF XY: 0.00000162 AC XY: 1 AN XY: 617830

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: 0.0000167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000555 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 28, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser6Pro variant in OTOG is classified as likely benign due to a lack of co nservation across species. Several species including mammals have Proline (Pro) at this position. ACMG/AMP Criteria applied: PM2, BP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.7
DANN	Benign	0.39
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.42	N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.94	N;.
REVEL	Benign	0.020
Sift	Benign	0.23	T;.
Sift4G	Benign	1.0	T;T
Vest4		0.14
MutPred		0.36		Loss of MoRF binding (P = 0.1206);Loss of MoRF binding (P = 0.1206);
MVP		0.092
ClinPred		0.055	T
GERP RS		-0.074
Varity_R		0.076
gMVP		0.088

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: rs773298682; hg19: chr11-17568935;