NM_001292063.2:c.8247C>G

Variant names:

• chr11-17641903-C-G
• rs778915475
• NM_001292063.2:c.8247C>G

Variant summary

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

The NM_001292063.2(OTOG):​c.8247C>G​(p.Asn2749Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N2749S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44

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.8247C>G	p.Asn2749Lys	missense_variant	Exon 52 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.8283C>G	p.Asn2761Lys	missense_variant	Exon 51 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.8247C>G	p.Asn2749Lys	missense_variant	Exon 52 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.8283C>G	p.Asn2761Lys	missense_variant	Exon 51 of 55	5		ENSP00000382323.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.055
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.078	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.1	D;.
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.67
MutPred		0.59		Gain of methylation at N2761 (P = 0.0182);.;
MVP		0.040
ClinPred		0.99	D
GERP RS		-7.2
Varity_R		0.89
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs778915475; hg19: chr11-17663450;