chr2-26464906-GCG-TAA

Variant names:

• chr2-26464906-GCG-TAA
• NM_194248.3:c.4921_4923delCGCinsTTA
• OTOF p.Arg1641Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_194248.3(OTOF):c.4921_4923delCGCinsTTA (p.Arg1641Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1641H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 48244); p.R1641= (synonymous): Likely_benign (ClinVar VariationId 2897397, 1 star); p.R1641= (synonymous): Likely_benign (ClinVar VariationId 4705054, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14
• 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	OTOF NM_194248.3	MANE Select	c.4921_4923delCGCinsTTA p.Arg1641Leu	missense	N/A	Prot: NP_919224.1 UniProt:
	OTOF NM_194323.3	MANE Plus Clinical	c.2620_2622delCGCinsTTA p.Arg874Leu	missense	N/A	Prot: NP_919304.1 UniProt:
	OTOF NM_001287489.2		c.4921_4923delCGCinsTTA p.Arg1641Leu	missense	N/A	Prot: NP_001274418.1 UniProt:

OTOF NM_194248.3

MANE Select

HGVSc / HGVSpc.4921_4923delCGCinsTTAp.Arg1641Leu

Exon rankN/A

missense

Prot: NP_919224.1UniProt: Q9HC10-1

OTOF NM_194323.3

MANE Plus Clinical

HGVSc / HGVSpc.2620_2622delCGCinsTTAp.Arg874Leu

Exon rankN/A

missense

Prot: NP_919304.1UniProt: Q9HC10-2

OTOF NM_001287489.2

HGVSc / HGVSpc.4921_4923delCGCinsTTAp.Arg1641Leu

Exon rankN/A

missense

Prot: NP_001274418.1UniProt: Q9HC10-5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	OTOF ENST00000272371.7	TSL:1MANE Select	c.4921_4923delCGCinsTTA p.Arg1641Leu	missense	N/A	Prot: ENSP00000272371.2 UniProt:
	OTOF ENST00000339598.8	TSL:1MANE Plus Clinical	c.2620_2622delCGCinsTTA p.Arg874Leu	missense	N/A	Prot: ENSP00000344521.3 UniProt:
	OTOF ENST00000402415.8	TSL:1	c.2680_2682delCGCinsTTA p.Arg894Leu	missense	N/A	Prot: ENSP00000383906.4 UniProt:

OTOF ENST00000272371.7

TSL:1MANE Select

HGVSc / HGVSpc.4921_4923delCGCinsTTAp.Arg1641Leu

Exon rankN/A

missense

Prot: ENSP00000272371.2UniProt: Q9HC10-1

OTOF ENST00000339598.8

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.2620_2622delCGCinsTTAp.Arg874Leu

Exon rankN/A

missense

Prot: ENSP00000344521.3UniProt: Q9HC10-2

OTOF ENST00000402415.8

TSL:1

HGVSc / HGVSpc.2680_2682delCGCinsTTAp.Arg894Leu

Exon rankN/A

missense

Prot: ENSP00000383906.4UniProt: A0A2U3TZT7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.1

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr2-26687774;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar