2-26476987-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_194248.3(OTOF):c.2580C>G(p.Val860Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,609,828 control chromosomes in the GnomAD database, including 144,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V860V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 13283 hom., cov: 29)

Exomes 𝑓: 0.41 ( 131690 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -2.81

Publications

21 publications found

Variant links:

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

OTOF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 2-26476987-G-C is Benign according to our data. Variant chr2-26476987-G-C is described in ClinVar as Benign. ClinVar VariationId is 21838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.82 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.2580C>G	p.Val860Val	synonymous_variant	Exon 22 of 47	ENST00000272371.7	NP_919224.1	Q9HC10-1
OTOF	NM_194323.3 link	c.339C>G	p.Val113Val	synonymous_variant	Exon 5 of 29	ENST00000339598.8	NP_919304.1	Q9HC10-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.2580C>G	p.Val860Val	synonymous_variant	Exon 22 of 47	1	NM_194248.3	ENSP00000272371.2		Q9HC10-1
OTOF	ENST00000339598.8 link	c.339C>G	p.Val113Val	synonymous_variant	Exon 5 of 29	1	NM_194323.3	ENSP00000344521.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60439

AN:

151520

Hom.:

13265

Cov.:

show subpopulations

Gnomad AFR

AF:

0.275

Gnomad AMI

AF:

0.416

Gnomad AMR

AF:

0.514

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.843

Gnomad SAS

AF:

0.505

Gnomad FIN

AF:

0.552

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.387

Gnomad OTH

AF:

0.378

GnomAD2 exomes

AF:

0.474

AC:

117447

AN:

247854

AF XY:

0.466

show subpopulations

Gnomad AFR exome

AF:

0.271

Gnomad AMR exome

AF:

0.650

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.851

Gnomad FIN exome

AF:

0.538

Gnomad NFE exome

AF:

0.384

Gnomad OTH exome

AF:

0.427

GnomAD4 exome

AF:

0.414

AC:

603433

AN:

1458192

Hom.:

131690

Cov.:

AF XY:

0.415

AC XY:

301032

AN XY:

725390

show subpopulations

African (AFR)

AF:

0.265

AC:

8866

AN:

33454

American (AMR)

AF:

0.630

AC:

28137

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

9224

AN:

26110

East Asian (EAS)

AF:

0.837

AC:

33204

AN:

39682

South Asian (SAS)

AF:

0.489

AC:

42119

AN:

86184

European-Finnish (FIN)

AF:

0.528

AC:

27369

AN:

51794

Middle Eastern (MID)

AF:

0.328

AC:

1889

AN:

5758

European-Non Finnish (NFE)

AF:

0.385

AC:

427139

AN:

1110266

Other (OTH)

AF:

0.423

AC:

25486

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

17818

35637

53455

71274

89092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13596

27192

40788

54384

67980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.399

AC:

60477

AN:

151636

Hom.:

13283

Cov.:

AF XY:

0.411

AC XY:

30470

AN XY:

74130

show subpopulations

African (AFR)

AF:

0.274

AC:

11347

AN:

41346

American (AMR)

AF:

0.515

AC:

7852

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.356

AC:

1235

AN:

3468

East Asian (EAS)

AF:

0.843

AC:

4307

AN:

5112

South Asian (SAS)

AF:

0.506

AC:

2437

AN:

4812

European-Finnish (FIN)

AF:

0.552

AC:

5809

AN:

10526

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.387

AC:

26220

AN:

67798

Other (OTH)

AF:

0.385

AC:

813

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1753

3505

5258

7010

8763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

572

1144

1716

2288

2860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.342

Hom.:

2829

Bravo

AF:

0.393

Asia WGS

AF:

0.637

AC:

2209

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 07, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:2Other:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.029

(source)

DANN

Benign

0.70

PhyloP100

-2.8

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over