11-17641026-G-C

Variant names:

• chr11-17641026-G-C
• rs189910531
• NM_001292063.2:c.8125G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001292063.2(OTOG):​c.8125G>C​(p.Asp2709His) variant causes a missense change. The variant allele was found at a frequency of 0.000000786 in 1,272,990 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2709N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.70
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.8125G>C	p.Asp2709His	missense	Exon 51 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.8161G>C	p.Asp2721His	missense	Exon 50 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.8125G>C	p.Asp2709His	missense	Exon 51 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.8161G>C	p.Asp2721His	missense	Exon 50 of 55	ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.86e-7 AC: 1 AN: 1272990 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 626408

African (AFR) AF: 0.00 AC: 0 AN: 27912

American (AMR) AF: 0.00 AC: 0 AN: 31956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20522

East Asian (EAS) AF: 0.00 AC: 0 AN: 24484

South Asian (SAS) AF: 0.00 AC: 0 AN: 78058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5080

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1000128

Other (OTH) AF: 0.0000200 AC: 1 AN: 49884

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.21
Sift	Uncertain	0.027	D
Sift4G	Pathogenic	0.0	D
Vest4		0.55
MutPred		0.55		Gain of catalytic residue at L2720 (P = 0.1949)
MVP		0.22
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.39
gMVP		0.88
Mutation Taster		=55/45	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

Other links and lift over

dbSNP: rs189910531; hg19: chr11-17662573;