2-26464893-G-A

Position:

chr2-26464893-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000272371.7(OTOF):c.4936C>T(p.Pro1646Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0343 in 1,600,522 control chromosomes in the GnomAD database, including 8,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1646T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.14 ( 4306 hom., cov: 32)

Exomes 𝑓: 0.023 ( 3929 hom. )

Consequence

OTOF
ENST00000272371.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.62

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014489889).

BP6

Variant 2-26464893-G-A is Benign according to our data. Variant chr2-26464893-G-A is described in ClinVar as [Benign]. Clinvar id is 21856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26464893-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.4936C>T	p.Pro1646Ser	missense_variant	39/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3 linkuse as main transcript	c.2635C>T	p.Pro879Ser	missense_variant	22/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.4936C>T	p.Pro1646Ser	missense_variant	39/47	1	NM_194248.3	ENSP00000272371	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.2635C>T	p.Pro879Ser	missense_variant	22/29	1	NM_194323.3	ENSP00000344521		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20919

AN:

151994

Hom.:

4284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.450

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0682

Gnomad ASJ

AF:

0.0404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.103

GnomAD3 exomes

AF:

0.0437

AC:

10621

AN:

243164

Hom.:

1661

AF XY:

0.0363

AC XY:

4778

AN XY:

131564

show subpopulations

Gnomad AFR exome

AF:

0.449

Gnomad AMR exome

AF:

0.0286

Gnomad ASJ exome

AF:

0.0457

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0313

Gnomad FIN exome

AF:

0.000371

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.0234

AC:

33854

AN:

1448410

Hom.:

3929

Cov.:

AF XY:

0.0225

AC XY:

16163

AN XY:

719826

show subpopulations

Gnomad4 AFR exome

AF:

0.463

Gnomad4 AMR exome

AF:

0.0338

Gnomad4 ASJ exome

AF:

0.0484

Gnomad4 EAS exome

AF:

0.0000511

Gnomad4 SAS exome

AF:

0.0319

Gnomad4 FIN exome

AF:

0.000488

Gnomad4 NFE exome

AF:

0.00935

Gnomad4 OTH exome

AF:

0.0443

GnomAD4 genome

AF:

0.138

AC:

20988

AN:

152112

Hom.:

4306

Cov.:

AF XY:

0.134

AC XY:

9959

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.450

Gnomad4 AMR

AF:

0.0681

Gnomad4 ASJ

AF:

0.0404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0269

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.102

Alfa

AF:

0.0235

Hom.:

596

Bravo

AF:

0.159

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.442

AC:

1949

ESP6500EA

AF:

0.0128

AC:

110

ExAC

AF:

0.0544

AC:

6601

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2017	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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;.;.;T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.00076

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

MetaRNN

Benign

0.0014

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

.;.;.;M;M;.

MutationTaster

Benign

0.0000014

P;P;P;P;P

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.5

N;N;.;N;N;.

REVEL

Benign

0.14

Sift

Benign

0.17

T;T;.;T;T;.

Sift4G

Benign

0.25

T;T;.;T;T;.

Polyphen

0.010

B;B;.;B;.;B

Vest4

0.40

MPC

0.29

ClinPred

0.021

GERP RS

4.9

Varity_R

0.15

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over