rs144594692

Variant names:

• chr2-26476917-C-G
• NM_194248.3:c.2650G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-26476917-C-G
• chr2-26476917-C-T

Variant summary

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

The NM_194248.3(OTOF):​c.2650G>C​(p.Ala884Pro) 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.

• Frequency: Genomes: not found (cov: 26)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.93

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2650G>C	p.Ala884Pro	missense_variant	Exon 22 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.409G>C	p.Ala137Pro	missense_variant	Exon 5 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2650G>C	p.Ala884Pro	missense_variant	Exon 22 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.409G>C	p.Ala137Pro	missense_variant	Exon 5 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	.;.;.;D;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.55	.;.;.;N;N;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;N;.;D;D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;D;.;D;D;.
Sift4G	Uncertain	0.0040	D;D;.;D;D;.
Polyphen		0.86	P;B;.;P;.;D
Vest4		0.59
MutPred		0.84		.;.;.;Gain of disorder (P = 0.0584);Gain of disorder (P = 0.0584);.;
MVP		0.89
MPC		0.63
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.92
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr2-26699785;