chr2-26476987-G-C

Position:

• chr2-26476987-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000272371.7(OTOF):​c.2580C>G​(p.Val860=) 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 ENST00000272371.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -2.81

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 -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 id is 21838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26476987-G-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2580C>G	p.Val860=	synonymous_variant	22/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.339C>G	p.Val113=	synonymous_variant	5/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2580C>G	p.Val860=	synonymous_variant	22/47	1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000339598.8	c.339C>G	p.Val113=	synonymous_variant	5/29	1	NM_194323.3	ENSP00000344521

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60439 AN: 151520 Hom.: 13265 Cov.: 29

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

GnomAD3 exomes AF: 0.474 AC: 117447 AN: 247854 Hom.: 30850 AF XY: 0.466 AC XY: 62669 AN XY: 134624

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 SAS exome AF: 0.488

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.: 36 AF XY: 0.415 AC XY: 301032 AN XY: 725390

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.630

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.837

Gnomad4 SAS exome AF: 0.489

Gnomad4 FIN exome AF: 0.528

Gnomad4 NFE exome AF: 0.385

Gnomad4 OTH exome AF: 0.423

GnomAD4 genome AF: 0.399 AC: 60477 AN: 151636 Hom.: 13283 Cov.: 29 AF XY: 0.411 AC XY: 30470 AN XY: 74130

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.843

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.552

Gnomad4 NFE AF: 0.387

Gnomad4 OTH AF: 0.385

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Mar 02, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.029
DANN	Benign	0.70

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

Other links and lift over

dbSNP: rs2272069; hg19: chr2-26699855; COSMIC: COSV55509806; COSMIC: COSV55509806;