chr2-26463970-G-A

Position:

• chr2-26463970-G-A

Variant summary

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

The NM_194248.3(OTOF):​c.5097C>T​(p.Ile1699=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,613,756 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (123 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (118 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.565

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=-0.28).
• BP6: Variant 2-26463970-G-A is Benign according to our data. Variant chr2-26463970-G-A is described in ClinVar as [Benign]. Clinvar id is 48252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.565 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.5097C>T	p.Ile1699=	synonymous_variant	40/47	ENST00000272371.7
OTOF	NM_194323.3	c.2796C>T	p.Ile932=	synonymous_variant	23/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.5097C>T	p.Ile1699=	synonymous_variant	40/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2796C>T	p.Ile932=	synonymous_variant	23/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3491 AN: 152142 Hom.: 121 Cov.: 33

Gnomad AFR AF: 0.0776

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00583 AC: 1458 AN: 250058 Hom.: 45 AF XY: 0.00420 AC XY: 568 AN XY: 135374

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00238 AC: 3480 AN: 1461496 Hom.: 118 Cov.: 32 AF XY: 0.00203 AC XY: 1476 AN XY: 727036

Gnomad4 AFR exome AF: 0.0832

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome AF: 0.0230 AC: 3502 AN: 152260 Hom.: 123 Cov.: 33 AF XY: 0.0221 AC XY: 1647 AN XY: 74454

Gnomad4 AFR AF: 0.0777

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0102 Hom.: 28

Bravo AF: 0.0263

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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	Apr 27, 2011	This variant is not expected to have clinical significance because it does not a lter an amino acid residue, is not located near a splice junction and has been r ecorded in dbSNP as a high frequency polymorphism in Black populations (rs123862 39. Yoruban = 10% [23/224 chromosomes], Luhya in Webuye, Kenya = 18% [32/180 chr omosomes]). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	5.6
DANN	Benign	0.91

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: rs12386239; hg19: chr2-26686838; COSMIC: COSV55516538;