rs876657556

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-17553506-G-C
• chr11-17553506-G-T

Variant summary

Our verdict is Likely benign. The variant received -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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S176S) has been classified 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
• Publications: 0 publications found

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]

OTOG Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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=0.13606107).
• 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 VariationId is 227787.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.527G>C	p.Ser176Thr	missense	Exon 6 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.563G>C	p.Ser188Thr	missense	Exon 5 of 55	NP_001264198.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.527G>C	p.Ser176Thr	missense	Exon 6 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.563G>C	p.Ser188Thr	missense	Exon 5 of 55	ENSP00000382323.2
	OTOG	ENST00000498332.5	TSL:5	n.433G>C		non_coding_transcript_exon	Exon 5 of 16

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.78	N
PhyloP100		1.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.051
Sift	Benign	0.26	T
Sift4G	Benign	0.20	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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs876657556; hg19: chr11-17575053;