2-26476258-C-G

Variant names:

• chr2-26476258-C-G
• rs4335905
• NM_194248.3:c.2736G>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.2736G>C​(p.Leu912Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,606,032 control chromosomes in the GnomAD database, including 205,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26656 hom., cov: 33)
  • Exomes 𝑓: 0.48 (178986 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -1.32

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-26476258-C-G is Benign according to our data. Variant chr2-26476258-C-G is described in ClinVar as [Benign]. Clinvar id is 21839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26476258-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2736G>C	p.Leu912Leu	synonymous_variant	Exon 23 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.495G>C	p.Leu165Leu	synonymous_variant	Exon 6 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2736G>C	p.Leu912Leu	synonymous_variant	Exon 23 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.495G>C	p.Leu165Leu	synonymous_variant	Exon 6 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86904 AN: 151892 Hom.: 26613 Cov.: 33

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.527

GnomAD3 exomes AF: 0.569 AC: 137121 AN: 240986 Hom.: 42666 AF XY: 0.554 AC XY: 73069 AN XY: 131932

Gnomad AFR exome AF: 0.727

Gnomad AMR exome AF: 0.732

Gnomad ASJ exome AF: 0.445

Gnomad EAS exome AF: 0.987

Gnomad SAS exome AF: 0.577

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.435

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.483 AC: 701814 AN: 1454022 Hom.: 178986 Cov.: 56 AF XY: 0.483 AC XY: 349760 AN XY: 723610

Gnomad4 AFR exome AF: 0.725

Gnomad4 AMR exome AF: 0.718

Gnomad4 ASJ exome AF: 0.450

Gnomad4 EAS exome AF: 0.977

Gnomad4 SAS exome AF: 0.578

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.436

Gnomad4 OTH exome AF: 0.516

GnomAD4 genome AF: 0.572 AC: 87012 AN: 152010 Hom.: 26656 Cov.: 33 AF XY: 0.581 AC XY: 43193 AN XY: 74286

Gnomad4 AFR AF: 0.724

Gnomad4 AMR AF: 0.633

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.983

Gnomad4 SAS AF: 0.592

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.532

Alfa AF: 0.468 Hom.: 5574

Bravo AF: 0.584

Asia WGS AF: 0.776 AC: 2695 AN: 3476

EpiCase AF: 0.441

EpiControl AF: 0.432

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not provided Benign:3

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

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:2 Other:1

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs4335905; hg19: chr2-26699126; COSMIC: COSV55500530; COSMIC: COSV55500530;