2-26477441-C-G

Variant names:

• chr2-26477441-C-G
• NM_194248.3:c.2381G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_194248.3(OTOF):​c.2381G>C​(p.Arg794Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R794H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26477441-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2381G>C	p.Arg794Pro	missense_variant	Exon 20 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.140G>C	p.Arg47Pro	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.2381G>C	p.Arg794Pro	missense_variant	Exon 20 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.140G>C	p.Arg47Pro	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	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;.;.;D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.2	.;.;.;M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.4	D;D;.;D;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;D;.
Polyphen		1.0	D;B;.;P;.;D
Vest4		0.91
MutPred		0.57		.;.;.;Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);.;
MVP		0.94
MPC		0.23
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.86

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: chr2-26700309;