2-26479599-CG-CGG

Variant names:

• chr2-26479599-C-CG
• rs397515590
• NM_194248.3:c.1966dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_194248.3(OTOF):​c.1966dupC​(p.Arg656ProfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOF NM_194248.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

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]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26479599-C-CG is Pathogenic according to our data. Variant chr2-26479599-C-CG is described in CliVar as Pathogenic. Clinvar id is 1377303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26479599-C-CG is described in CliVar as Pathogenic. Clinvar id is 1377303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26479599-C-CG is described in CliVar as Pathogenic. Clinvar id is 1377303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26479599-C-CG is described in CliVar as Pathogenic. Clinvar id is 1377303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.1966dupC	p.Arg656ProfsTer7	frameshift_variant	Exon 17 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.1966dupC	p.Arg656ProfsTer7	frameshift_variant	Exon 17 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.1966dupC	p.Arg656ProfsTer7	frameshift_variant	Exon 17 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.1966dupC	p.Arg656ProfsTer7	frameshift_variant	Exon 17 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg656Profs*7) in the OTOF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OTOF are known to be pathogenic (PMID: 18381613, 19250381, 22575033). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with auditory neuropathy (PMID: 30368385). ClinVar contains an entry for this variant (Variation ID: 1377303). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

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

Other links and lift over

dbSNP: rs397515590; hg19: chr2-26702467;