2-26476987-G-C

Variant names:

• chr2-26476987-G-C
• rs2272069
• NM_194248.3:c.2580C>G

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.2580C>G​(p.Val860Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,609,828 control chromosomes in the GnomAD database, including 144,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V860V) has been classified as Likely benign. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.40 (13283 hom., cov: 29)
  • Exomes 𝑓: 0.41 (131690 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -2.81
• Publications: 21 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

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 2-26476987-G-C is Benign according to our data. Variant chr2-26476987-G-C is described in ClinVar as Benign. ClinVar VariationId is 21838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 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.2580C>G	p.Val860Val	synonymous	Exon 22 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.339C>G	p.Val113Val	synonymous	Exon 5 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2580C>G	p.Val860Val	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.2580C>G	p.Val860Val	synonymous	Exon 22 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.339C>G	p.Val113Val	synonymous	Exon 5 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.339C>G	p.Val113Val	synonymous	Exon 4 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60439 AN: 151520 Hom.: 13265 Cov.: 29

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.474 AC: 117447 AN: 247854 AF XY: 0.466

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.851

Gnomad FIN exome AF: 0.538

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.414 AC: 603433 AN: 1458192 Hom.: 131690 Cov.: 36 AF XY: 0.415 AC XY: 301032 AN XY: 725390

African (AFR) AF: 0.265 AC: 8866 AN: 33454

American (AMR) AF: 0.630 AC: 28137 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9224 AN: 26110

East Asian (EAS) AF: 0.837 AC: 33204 AN: 39682

South Asian (SAS) AF: 0.489 AC: 42119 AN: 86184

European-Finnish (FIN) AF: 0.528 AC: 27369 AN: 51794

Middle Eastern (MID) AF: 0.328 AC: 1889 AN: 5758

European-Non Finnish (NFE) AF: 0.385 AC: 427139 AN: 1110266

Other (OTH) AF: 0.423 AC: 25486 AN: 60296

GnomAD4 genome AF: 0.399 AC: 60477 AN: 151636 Hom.: 13283 Cov.: 29 AF XY: 0.411 AC XY: 30470 AN XY: 74130

African (AFR) AF: 0.274 AC: 11347 AN: 41346

American (AMR) AF: 0.515 AC: 7852 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3468

East Asian (EAS) AF: 0.843 AC: 4307 AN: 5112

South Asian (SAS) AF: 0.506 AC: 2437 AN: 4812

European-Finnish (FIN) AF: 0.552 AC: 5809 AN: 10526

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26220 AN: 67798

Other (OTH) AF: 0.385 AC: 813 AN: 2110

Alfa AF: 0.342 Hom.: 2829

Bravo AF: 0.393

Asia WGS AF: 0.637 AC: 2209 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Autosomal recessive nonsyndromic hearing loss 9 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.029
DANN	Benign	0.70
PhyloP100		-2.8
Mutation Taster		=88/12	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: rs2272069; hg19: chr2-26699855; COSMIC: COSV55509806; COSMIC: COSV55509806;