2-26467406-C-G

Position:

• chr2-26467406-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_194248.3(OTOF):​c.4186G>C​(p.Glu1396Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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: 2.65

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16639271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4186G>C	p.Glu1396Gln	missense_variant	34/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.1885G>C	p.Glu629Gln	missense_variant	17/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4186G>C	p.Glu1396Gln	missense_variant	34/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.1885G>C	p.Glu629Gln	missense_variant	17/29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.064	.;.;.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.5	.;.;.;L;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.43	N;N;.;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.41	T;T;.;T;T;.
Sift4G	Benign	0.20	T;T;.;T;T;.
Polyphen		0.77	P;B;.;B;.;B
Vest4		0.41
MutPred		0.21		.;.;.;Gain of MoRF binding (P = 0.033);Gain of MoRF binding (P = 0.033);.;
MVP		0.86
MPC		0.21
ClinPred		0.27	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-26690274;