rs2272068

Variant names:

• chr2-26476954-G-A
• rs2272068
• NM_194248.3:c.2613C>T

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.2613C>T​(p.Leu871Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,611,540 control chromosomes in the GnomAD database, including 940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (136 hom., cov: 26)
  • Exomes 𝑓: 0.021 (804 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0400
• Publications: 6 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=-0.4).
• BP6: Variant 2-26476954-G-A is Benign according to our data. Variant chr2-26476954-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2613C>T	p.Leu871Leu	synonymous_variant	Exon 22 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.372C>T	p.Leu124Leu	synonymous_variant	Exon 5 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2613C>T	p.Leu871Leu	synonymous_variant	Exon 22 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.372C>T	p.Leu124Leu	synonymous_variant	Exon 5 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5252 AN: 151530 Hom.: 134 Cov.: 26

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.00318

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0344 AC: 8576 AN: 249658 AF XY: 0.0334

Gnomad AFR exome AF: 0.0523

Gnomad AMR exome AF: 0.0395

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.0389

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0214 AC: 31233 AN: 1459894 Hom.: 804 Cov.: 31 AF XY: 0.0219 AC XY: 15905 AN XY: 726256

African (AFR) AF: 0.0557 AC: 1864 AN: 33474

American (AMR) AF: 0.0402 AC: 1797 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26132

East Asian (EAS) AF: 0.140 AC: 5566 AN: 39690

South Asian (SAS) AF: 0.0442 AC: 3814 AN: 86250

European-Finnish (FIN) AF: 0.0347 AC: 1803 AN: 51898

Middle Eastern (MID) AF: 0.0173 AC: 100 AN: 5768

European-Non Finnish (NFE) AF: 0.0131 AC: 14526 AN: 1111612

Other (OTH) AF: 0.0284 AC: 1717 AN: 60354

GnomAD4 genome AF: 0.0347 AC: 5266 AN: 151646 Hom.: 136 Cov.: 26 AF XY: 0.0363 AC XY: 2694 AN XY: 74166

African (AFR) AF: 0.0529 AC: 2185 AN: 41316

American (AMR) AF: 0.0364 AC: 556 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 11 AN: 3462

East Asian (EAS) AF: 0.140 AC: 715 AN: 5090

South Asian (SAS) AF: 0.0493 AC: 236 AN: 4784

European-Finnish (FIN) AF: 0.0421 AC: 445 AN: 10578

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0138 AC: 933 AN: 67850

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0185 Hom.: 29

Bravo AF: 0.0357

Asia WGS AF: 0.0960 AC: 333 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 03, 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. -

Feb 19, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.4
DANN	Benign	0.77
PhyloP100		-0.040
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2272068; hg19: chr2-26699822; COSMIC: COSV55501172; COSMIC: COSV55501172;