2-26476291-C-T

Position:

chr2-26476291-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_194248.3(OTOF):c.2703G>A(p.Ser901=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,602,782 control chromosomes in the GnomAD database, including 979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 170 hom., cov: 32)

Exomes 𝑓: 0.022 ( 809 hom. )

Consequence

OTOF
NM_194248.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.33

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 2-26476291-C-T is Benign according to our data. Variant chr2-26476291-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26476291-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3 linkuse as main transcript	c.2703G>A	p.Ser901=	synonymous_variant	23/47	ENST00000272371.7
OTOF	NM_194323.3 linkuse as main transcript	c.462G>A	p.Ser154=	synonymous_variant	6/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7 linkuse as main transcript	c.2703G>A	p.Ser901=	synonymous_variant	23/47	1	NM_194248.3	A1	Q9HC10-1
OTOF	ENST00000339598.8 linkuse as main transcript	c.462G>A	p.Ser154=	synonymous_variant	6/29	1	NM_194323.3		Q9HC10-2

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5924

AN:

152096

Hom.:

167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0670

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.0407

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.135

Gnomad SAS

AF:

0.0497

Gnomad FIN

AF:

0.0419

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.0325

GnomAD3 exomes

AF:

0.0363

AC:

8397

AN:

231158

Hom.:

303

AF XY:

0.0347

AC XY:

4432

AN XY:

127846

show subpopulations

Gnomad AFR exome

AF:

0.0712

Gnomad AMR exome

AF:

0.0414

Gnomad ASJ exome

AF:

0.00195

Gnomad EAS exome

AF:

0.135

Gnomad SAS exome

AF:

0.0446

Gnomad FIN exome

AF:

0.0410

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0260

GnomAD4 exome

AF:

0.0216

AC:

31335

AN:

1450570

Hom.:

809

Cov.:

AF XY:

0.0221

AC XY:

15927

AN XY:

721932

show subpopulations

Gnomad4 AFR exome

AF:

0.0694

Gnomad4 AMR exome

AF:

0.0422

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.135

Gnomad4 SAS exome

AF:

0.0443

Gnomad4 FIN exome

AF:

0.0340

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.0294

GnomAD4 genome

AF:

0.0390

AC:

5943

AN:

152212

Hom.:

170

Cov.:

AF XY:

0.0407

AC XY:

3026

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0673

Gnomad4 AMR

AF:

0.0407

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.135

Gnomad4 SAS

AF:

0.0491

Gnomad4 FIN

AF:

0.0419

Gnomad4 NFE

AF:

0.0138

Gnomad4 OTH

AF:

0.0322

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0404

Asia WGS

AF:

0.0990

AC:

340

AN:

3462

EpiCase

AF:

0.0134

EpiControl

AF:

0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -

Autosomal recessive nonsyndromic hearing loss 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.039

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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