11-17606135-G-C

Variant names:

• chr11-17606135-G-C
• NM_001292063.2:c.4156G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001292063.2(OTOG):​c.4156G>C​(p.Asp1386His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000727 in 1,374,806 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.76

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.4156G>C	p.Asp1386His	missense_variant, splice_region_variant	Exon 33 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.4192G>C	p.Asp1398His	missense_variant, splice_region_variant	Exon 32 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.4156G>C	p.Asp1386His	missense_variant, splice_region_variant	Exon 33 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.4192G>C	p.Asp1398His	missense_variant, splice_region_variant	Exon 32 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.1494G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 22	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1374806 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 674144

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: 0.0000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.047	D;T
Vest4		0.38
MutPred		0.47		Loss of ubiquitination at K1400 (P = 0.0349);.;
MVP		0.30
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.24
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-17627682;