chr2-26479640-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_194248.3(OTOF):c.1926C>T(p.Asn642Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,612,446 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 58 hom., cov: 34)

Exomes 𝑓: 0.022 ( 431 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0160

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 2-26479640-G-A is Benign according to our data. Variant chr2-26479640-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.016 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0258 (3931/152352) while in subpopulation AFR AF = 0.0445 (1850/41586). AF 95% confidence interval is 0.0428. There are 58 homozygotes in GnomAd4. There are 1828 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3 link	c.1926C>T	p.Asn642Asn	synonymous_variant	Exon 17 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2 link	c.1926C>T	p.Asn642Asn	synonymous_variant	Exon 17 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 link	c.1926C>T	p.Asn642Asn	synonymous_variant	Exon 17 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7 link	c.1926C>T	p.Asn642Asn	synonymous_variant	Exon 17 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes

AF:

0.0258

AC:

3929

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0445

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0194

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0208

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.0186

AC:

4637

AN:

249340

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.0460

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0221

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0221

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0217

AC:

31691

AN:

1460094

Hom.:

431

Cov.:

AF XY:

0.0210

AC XY:

15270

AN XY:

726228

show subpopulations

African (AFR)

AF:

0.0471

AC:

1577

AN:

33470

American (AMR)

AF:

0.0138

AC:

616

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

550

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.00356

AC:

307

AN:

86246

European-Finnish (FIN)

AF:

0.0229

AC:

1194

AN:

52128

Middle Eastern (MID)

AF:

0.0222

AC:

128

AN:

5764

European-Non Finnish (NFE)

AF:

0.0234

AC:

26017

AN:

1111622

Other (OTH)

AF:

0.0216

AC:

1301

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1599

3198

4796

6395

7994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1000

2000

3000

4000

5000

<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:

0.0258

AC:

3931

AN:

152352

Hom.:

Cov.:

AF XY:

0.0245

AC XY:

1828

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0445

AC:

1850

AN:

41586

American (AMR)

AF:

0.0193

AC:

296

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0200

AC:

212

AN:

10618

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0208

AC:

1413

AN:

68028

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

199

398

598

797

996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0235

Hom.:

Bravo

AF:

0.0273

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0244

EpiControl

AF:

0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 31, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 06, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asn642Asn in exon 17 of OTOF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs72853741 ? no frequency data), has been f ound in 5/150 (3%) cases in our laboratory (two of whom have other hearing loss etiologies), and is reported as benign in two publications (Smith 2008, Varga 20 06).

Jan 02, 2018

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.

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

1.3

(source)

DANN

Benign

0.48

PhyloP100

0.016

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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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