2-26516555-T-C

Variant names:

• chr2-26516555-T-C
• rs11687696
• NM_194248.3:c.372A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.372A>G​(p.Thr124Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,611,062 control chromosomes in the GnomAD database, including 70,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5628 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64792 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -9.09
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 2-26516555-T-C is Benign according to our data. Variant chr2-26516555-T-C is described in ClinVar as Benign. ClinVar VariationId is 21847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.372A>G	p.Thr124Thr	synonymous_variant	Exon 5 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.372A>G	p.Thr124Thr	synonymous_variant	Exon 5 of 46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.372A>G	p.Thr124Thr	synonymous_variant	Exon 5 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.372A>G	p.Thr124Thr	synonymous_variant	Exon 5 of 46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36615 AN: 151986 Hom.: 5627 Cov.: 32

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.301 AC: 75120 AN: 249402 AF XY: 0.299

Gnomad AFR exome AF: 0.0629

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.292 AC: 425708 AN: 1458958 Hom.: 64792 Cov.: 43 AF XY: 0.291 AC XY: 211009 AN XY: 725960

African (AFR) AF: 0.0580 AC: 1943 AN: 33480

American (AMR) AF: 0.309 AC: 13831 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5308 AN: 26134

East Asian (EAS) AF: 0.467 AC: 18558 AN: 39700

South Asian (SAS) AF: 0.248 AC: 21377 AN: 86256

European-Finnish (FIN) AF: 0.401 AC: 20290 AN: 50650

Middle Eastern (MID) AF: 0.190 AC: 1095 AN: 5768

European-Non Finnish (NFE) AF: 0.293 AC: 326249 AN: 1111884

Other (OTH) AF: 0.283 AC: 17057 AN: 60366

GnomAD4 genome AF: 0.241 AC: 36638 AN: 152104 Hom.: 5628 Cov.: 32 AF XY: 0.247 AC XY: 18357 AN XY: 74346

African (AFR) AF: 0.0696 AC: 2889 AN: 41532

American (AMR) AF: 0.250 AC: 3827 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3466

East Asian (EAS) AF: 0.518 AC: 2664 AN: 5144

South Asian (SAS) AF: 0.263 AC: 1268 AN: 4824

European-Finnish (FIN) AF: 0.412 AC: 4361 AN: 10584

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20081 AN: 67956

Other (OTH) AF: 0.223 AC: 470 AN: 2108

Alfa AF: 0.271 Hom.: 1855

Bravo AF: 0.224

Asia WGS AF: 0.432 AC: 1502 AN: 3478

EpiCase AF: 0.282

EpiControl AF: 0.277

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -

Mar 02, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.013
DANN	Benign	0.26
PhyloP100		-9.1
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11687696; hg19: chr2-26739423; COSMIC: COSV55510690;