2-26470685-CCTTCTT-CCTTCTTCTT

Variant names:

• chr2-26470685-C-CCTT
• rs368148603
• NM_194248.3:c.3928_3930dupAAG

Variant summary

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

The NM_194248.3(OTOF):​c.3928_3930dupAAG​(p.Lys1310dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,609,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: OTOF NM_194248.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.253

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3928_3930dupAAG	p.Lys1310dup	conservative_inframe_insertion	Exon 32 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.1627_1629dupAAG	p.Lys543dup	conservative_inframe_insertion	Exon 15 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3928_3930dupAAG	p.Lys1310dup	conservative_inframe_insertion	Exon 32 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.1627_1629dupAAG	p.Lys543dup	conservative_inframe_insertion	Exon 15 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 151970 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000189 AC: 47 AN: 248192 Hom.: 0 AF XY: 0.000164 AC XY: 22 AN XY: 134272

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000819

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000148 AC: 215 AN: 1457492 Hom.: 0 Cov.: 33 AF XY: 0.000143 AC XY: 104 AN XY: 725250

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000399

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152084 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74336

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000121

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Jan 29, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame insertion of one amino acid in a repetitive region with no known function; This variant is associated with the following publications: (PMID: 34426522, 35114279, 25326637) -

Jun 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3928_3930dup, results in the insertion of 1 amino acid(s) of the OTOF protein (p.Lys1310dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768338261, gnomAD 0.08%). This variant has been observed in individual(s) with clinical features of OTOF-related conditions (PMID: 25326637). ClinVar contains an entry for this variant (Variation ID: 229079). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOF: PM4:Supporting -

not specified Uncertain:1

Mar 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys1310dup variant in OTOF has been previously reported in one individual with hearing loss and multiple congenital anomalies who was compound heterozygou s for a second likely pathogenic variant in OTOF (Lee 2014). This variant has a lso been identified in 6/8612 of East Asian chromosomes and 8/16414 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs768338261). Although this variant has been seen in the general po pulation, its frequency is not high enough to rule out a pathogenic role. This v ariant results in an in-frame insertion of one lysine (Lys) residue in a lysine tract and does not alter the amino acid reading frame. It is unclear if this ins ertion will impact the protein. In summary, the clinical significance of the p.L ys1310dup variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Apr 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368148603; hg19: chr2-26693553;