rs766172178

Variant names:

• chr11-17553374-C-T
• rs766172178
• NM_001292063.2:c.395C>T
• OTOG p.Ala132Val

Your query was ambiguous. Multiple possible variants found:

• chr11-17553374-C-T
• chr11-17553374-C-A
• chr11-17553374-C-G

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.395C>T​(p.Ala132Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000229 in 1,311,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A132A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.981
• Publications: 1 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: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• 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=0.09464091).
• BP6: Variant 11-17553374-C-T is Benign according to our data. Variant chr11-17553374-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 227781.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	NM_001292063.2	MANE Select	c.395C>T	p.Ala132Val	missense	Exon 6 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.431C>T	p.Ala144Val	missense	Exon 5 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.395C>T	p.Ala132Val	missense	Exon 6 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.431C>T	p.Ala144Val	missense	Exon 5 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000428619.1	TSL:3	c.212C>T	p.Ala71Val	missense	Exon 4 of 4	ENSP00000399057.2	C9IZ84

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000229 AC: 3 AN: 1311776 Hom.: 0 Cov.: 32 AF XY: 0.00000157 AC XY: 1 AN XY: 636820

African (AFR) AF: 0.00 AC: 0 AN: 28826

American (AMR) AF: 0.00 AC: 0 AN: 22856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19470

East Asian (EAS) AF: 0.00 AC: 0 AN: 34878

South Asian (SAS) AF: 0.00 AC: 0 AN: 64710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5274

European-Non Finnish (NFE) AF: 0.00000289 AC: 3 AN: 1036528

Other (OTH) AF: 0.00 AC: 0 AN: 54224

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	0.094
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.98
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.036
Sift	Benign	0.48	T
Sift4G	Benign	1.0	T
Varity_R		0.025
gMVP		0.18
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766172178;

hg19: chr11-17574921;