2-26461811-G-C

Variant names:

• chr2-26461811-G-C
• rs116990436
• NM_194248.3:c.5418C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_194248.3(OTOF):​c.5418C>G​(p.Ile1806Met) 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. 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: -2.22

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.

• PM1: In a domain C2 7 (size 151) in uniprot entity OTOF_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_194248.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21062106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5418C>G	p.Ile1806Met	missense_variant	Exon 43 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3117C>G	p.Ile1039Met	missense_variant	Exon 26 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5418C>G	p.Ile1806Met	missense_variant	Exon 43 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3117C>G	p.Ile1039Met	missense_variant	Exon 26 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;.;T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.88	.;.;.;L;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N;N;.;N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.37	T;T;.;T;T;.
Sift4G	Benign	0.42	T;T;.;T;T;.
Polyphen		0.13	B;B;.;P;.;D
Vest4		0.52
MutPred		0.49		.;.;.;Gain of catalytic residue at I1806 (P = 0.0017);Gain of catalytic residue at I1806 (P = 0.0017);.;
MVP		0.65
MPC		0.49
ClinPred		0.42	T
GERP RS		-2.5
Varity_R		0.15
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116990436; hg19: chr2-26684679;