2-26467120-C-T

Variant names:

• chr2-26467120-C-T
• rs80214437
• NM_194248.3:c.4341G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.4341G>A​(p.Glu1447Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,613,820 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (144 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.802
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-26467120-C-T is Benign according to our data. Variant chr2-26467120-C-T is described in ClinVar as Benign. ClinVar VariationId is 48234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.802 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0855 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.4341G>A	p.Glu1447Glu	synonymous	Exon 35 of 47	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2040G>A	p.Glu680Glu	synonymous	Exon 18 of 29	NP_919304.1
	OTOF	NM_001287489.2		c.4341G>A	p.Glu1447Glu	synonymous	Exon 35 of 46	NP_001274418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.4341G>A	p.Glu1447Glu	synonymous	Exon 35 of 47	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2040G>A	p.Glu680Glu	synonymous	Exon 18 of 29	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.2100G>A	p.Glu700Glu	synonymous	Exon 17 of 29	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3860 AN: 152076 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00656 AC: 1648 AN: 251074 AF XY: 0.00465

Gnomad AFR exome AF: 0.0883

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00256 AC: 3747 AN: 1461626 Hom.: 144 Cov.: 35 AF XY: 0.00219 AC XY: 1590 AN XY: 727134

African (AFR) AF: 0.0915 AC: 3065 AN: 33480

American (AMR) AF: 0.00550 AC: 246 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53156

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000665 AC: 74 AN: 1112008

Other (OTH) AF: 0.00560 AC: 338 AN: 60396

GnomAD4 genome AF: 0.0254 AC: 3859 AN: 152194 Hom.: 170 Cov.: 32 AF XY: 0.0249 AC XY: 1851 AN XY: 74410

African (AFR) AF: 0.0878 AC: 3643 AN: 41472

American (AMR) AF: 0.0112 AC: 172 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00943 Hom.: 28

Bravo AF: 0.0290

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 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.

Jun 09, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu1447Glu in exon 35 of OTOF: This variant is classified as benign based on its high frequency in the general population (rs80214437; heterozygous frequency of 5.9% and homozygous frequency of 0.4%).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jan 23, 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

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.5
DANN	Benign	0.54
PhyloP100		0.80
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs80214437; hg19: chr2-26689988;