rs876657941

Variant names:

• chr11-17633868-A-G
• rs876657941
• NM_001292063.2:c.7261A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001292063.2(OTOG):​c.7261A>G​(p.Lys2421Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7261A>G	p.Lys2421Glu	missense_variant	Exon 43 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7297A>G	p.Lys2433Glu	missense_variant	Exon 42 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7261A>G	p.Lys2421Glu	missense_variant	Exon 43 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.7297A>G	p.Lys2433Glu	missense_variant	Exon 42 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.4599A>G		non_coding_transcript_exon_variant	Exon 19 of 22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1383624 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 680960

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 23, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys2433Glu variant in OTOG has not been previously reported in individuals with hearing loss. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Lys2433Gly variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.26
Sift	Benign	0.44	T;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.54
MutPred		0.64		Loss of methylation at K2433 (P = 0.0029);.;
MVP		0.26
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.81

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: rs876657941; hg19: chr11-17655415;