2-26464907-C-A

Variant names:

• chr2-26464907-C-A
• rs200283244
• NM_194248.3:c.4922G>T
• OTOF p.Arg1641Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NM_194248.3(OTOF):c.4922G>T (p.Arg1641Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000376 (AC=6) in the gnomAD database across 1,597,354 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000193. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14
• Publications: 2 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 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

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.4922G>T p.Arg1641Leu	missense	Exon 39 of 47	Prot: NP_919224.1 UniProt:
	OTOF NM_194323.3	MANE Plus Clinical	c.2621G>T p.Arg874Leu	missense	Exon 22 of 29	Prot: NP_919304.1 UniProt:
	OTOF NM_001287489.2		c.4922G>T p.Arg1641Leu	missense	Exon 39 of 46	Prot: NP_001274418.1 UniProt:

OTOF NM_194248.3

MANE Select

HGVSc / HGVSpc.4922G>Tp.Arg1641Leu

Exon rankExon 39 of 47

missense

Prot: NP_919224.1UniProt: Q9HC10-1

OTOF NM_194323.3

MANE Plus Clinical

HGVSc / HGVSpc.2621G>Tp.Arg874Leu

Exon rankExon 22 of 29

missense

Prot: NP_919304.1UniProt: Q9HC10-2

OTOF NM_001287489.2

HGVSc / HGVSpc.4922G>Tp.Arg1641Leu

Exon rankExon 39 of 46

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.4922G>T p.Arg1641Leu	missense	Exon 39 of 47	Prot: ENSP00000272371.2 UniProt:
	OTOF ENST00000339598.8	TSL:1MANE Plus Clinical	c.2621G>T p.Arg874Leu	missense	Exon 22 of 29	Prot: ENSP00000344521.3 UniProt:
	OTOF ENST00000402415.8	TSL:1	c.2681G>T p.Arg894Leu	missense	Exon 21 of 29	Prot: ENSP00000383906.4 UniProt:

OTOF ENST00000272371.7

TSL:1MANE Select

HGVSc / HGVSpc.4922G>Tp.Arg1641Leu

Exon rankExon 39 of 47

missense

Prot: ENSP00000272371.2UniProt: Q9HC10-1

OTOF ENST00000339598.8

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.2621G>Tp.Arg874Leu

Exon rankExon 22 of 29

missense

Prot: ENSP00000344521.3UniProt: Q9HC10-2

OTOF ENST00000402415.8

TSL:1

HGVSc / HGVSpc.2681G>Tp.Arg894Leu

Exon rankExon 21 of 29

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152140	Cov:33
GnomAD2 exomes	AF: 0.00	AC:0	Hom:	AN:240798	Cov:
GnomAD4 exome	AF: 0.00000277	AC:4	Hom:0	AN:1445214	Cov:31
GnomAD4 genome Warning	AF: 0.0000131	AC:2	Hom:0	AN:152140	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:174650	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.65
GPN-Star LLR	N/A	-4.7
GPN-Star score	N/A	4.7
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.58	T
Mutation Taster	N/A	25/75	disease causing
MutationAssessor	Uncertain	2.7	M
PhyloP100	Uncertain	4.1
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Varity_R	N/A	0.36
VESM-3B	Benign	-9.2

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs200283244;

hg19: chr2-26687775;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar