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, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.2613C>T	p.Leu871Leu	synonymous	Exon 22 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.372C>T	p.Leu124Leu	synonymous	Exon 5 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2613C>T	p.Leu871Leu	synonymous	Exon 22 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2613C>T	p.Leu871Leu	synonymous	Exon 22 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.372C>T	p.Leu124Leu	synonymous	Exon 5 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.372C>T	p.Leu124Leu	synonymous	Exon 4 of 29	ENSP00000383906.4	A0A2U3TZT7

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

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;