NM_001292063.2:c.527G>C

Variant names:

• chr11-17553506-G-C
• rs876657556
• NM_001292063.2:c.527G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001292063.2(OTOG):​c.527G>C​(p.Ser176Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13606107).
• BP6: Variant 11-17553506-G-C is Benign according to our data. Variant chr11-17553506-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227787.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.527G>C	p.Ser176Thr	missense_variant	Exon 6 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.563G>C	p.Ser188Thr	missense_variant	Exon 5 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.527G>C	p.Ser176Thr	missense_variant	Exon 6 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.563G>C	p.Ser188Thr	missense_variant	Exon 5 of 55	5		ENSP00000382323.2
OTOG	ENST00000498332.5	n.433G>C		non_coding_transcript_exon_variant	Exon 5 of 16	5
OTOG	ENST00000428619.1	c.*62G>C		downstream_gene_variant		3		ENSP00000399057.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser188Thr in exon 5 of OTOG: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 18 mammals have a Threonine (Thr) at this position. In addition, computation al prediction tools do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.78	N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.88	N;.
REVEL	Benign	0.051
Sift	Benign	0.26	T;.
Sift4G	Benign	0.20	T;T
Vest4		0.086
MutPred		0.64		Loss of disorder (P = 0.0607);.;
MVP		0.29
ClinPred		0.057	T
GERP RS		2.3
Varity_R		0.057
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876657556; hg19: chr11-17575053;