11-17613688-G-C

Variant names:

• chr11-17613688-G-C
• rs555068328
• NM_001292063.2:c.6515G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001292063.2(OTOG):​c.6515G>C​(p.Arg2172Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.6515G>C	p.Arg2172Pro	missense_variant	Exon 39 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.6551G>C	p.Arg2184Pro	missense_variant	Exon 38 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.6515G>C	p.Arg2172Pro	missense_variant	Exon 39 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.6551G>C	p.Arg2184Pro	missense_variant	Exon 38 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.3853G>C		non_coding_transcript_exon_variant	Exon 15 of 22	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398482 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689744

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: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.81
MutPred		0.67		Gain of glycosylation at T2181 (P = 0.0314);.;
MVP		0.53
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs555068328; hg19: chr11-17635235;