2-26477421-C-T

Variant names:

• chr2-26477421-C-T
• NM_194248.3:c.2401G>A

Variant summary

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

The NM_194248.3(OTOF):​c.2401G>A​(p.Glu801Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.86

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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
OTOF	NM_194248.3	c.2401G>A	p.Glu801Lys	missense_variant	Exon 20 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.160G>A	p.Glu54Lys	missense_variant	Exon 3 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2401G>A	p.Glu801Lys	missense_variant	Exon 20 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.160G>A	p.Glu54Lys	missense_variant	Exon 3 of 29	1	NM_194323.3	ENSP00000344521.3

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	0.72
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	.;.;.;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.010	D;D;.;D;D;.
Sift4G	Uncertain	0.0080	D;D;.;D;D;.
Polyphen		1.0	D;P;.;D;.;D
Vest4		0.90
MutPred		0.23		.;.;.;Loss of ubiquitination at K796 (P = 0.0236);Loss of ubiquitination at K796 (P = 0.0236);.;
MVP		0.95
MPC		0.67
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.66
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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: chr2-26700289;