2-26477441-C-T

Variant names:

• chr2-26477441-C-T
• rs80356592
• NM_194248.3:c.2381G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.2381G>A​(p.Arg794His) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,596,440 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (8 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5 O:1
• Conservation: PhyloP100: 5.89
• Publications: 14 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014693469).
• BP6: Variant 2-26477441-C-T is Benign according to our data. Variant chr2-26477441-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21835.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00127 (193/152174) while in subpopulation NFE AF = 0.00209 (142/67992). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 91 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2381G>A	p.Arg794His	missense_variant	Exon 20 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.140G>A	p.Arg47His	missense_variant	Exon 3 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2381G>A	p.Arg794His	missense_variant	Exon 20 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.140G>A	p.Arg47His	missense_variant	Exon 3 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00109 AC: 241 AN: 220574 AF XY: 0.00115

Gnomad AFR exome AF: 0.000521

Gnomad AMR exome AF: 0.000788

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00208 AC: 2999 AN: 1444266 Hom.: 8 Cov.: 33 AF XY: 0.00198 AC XY: 1420 AN XY: 716558

African (AFR) AF: 0.000180 AC: 6 AN: 33254

American (AMR) AF: 0.000920 AC: 39 AN: 42412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39060

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83216

European-Finnish (FIN) AF: 0.0000982 AC: 5 AN: 50896

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5734

European-Non Finnish (NFE) AF: 0.00257 AC: 2834 AN: 1104204

Other (OTH) AF: 0.00186 AC: 111 AN: 59742

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74390

African (AFR) AF: 0.000530 AC: 22 AN: 41526

American (AMR) AF: 0.00157 AC: 24 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 67992

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00172 Hom.: 1

Bravo AF: 0.00144

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000922 AC: 4

ESP6500EA AF: 0.00210 AC: 18

ExAC AF: 0.000907 AC: 109

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OTOF: PP3, BS1:Supporting -

Jun 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 23208854, 22906306, 20301429, 12525542, 16371502) -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2020

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1 Benign:1 Other:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:2

Aug 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg794His in exon 20 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.2% (71/26210) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356592). -

Jul 08, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: OTOF c.2381G>A (p.Arg794His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 220574 control chromosomes (gnomAD), predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2381G>A has been found in the heterozygous state (with no second OTOF variant reported) in individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Varga_2006, Schrauwen_2013). These reports do not provide unequivocal conclusions about association of the variant with Nonsyndromic Hearing Loss And Deafness, Type 9. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	.;.;.;D;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.015	T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	.;.;.;M;M;.
PhyloP100		5.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D;D;.;D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.024	D;D;.;D;D;.
Sift4G	Uncertain	0.019	D;D;.;D;D;.
Polyphen		0.94	P;B;.;D;.;D
Vest4		0.88
MVP		0.93
MPC		0.57
ClinPred		0.054	T
GERP RS		4.7
Varity_R		0.45
gMVP		0.63
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs80356592; hg19: chr2-26700309;