2-26476291-C-T

Variant names:

• chr2-26476291-C-T
• rs4997760
• NM_194248.3:c.2703G>A

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.2703G>A​(p.Ser901Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,602,782 control chromosomes in the GnomAD database, including 979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (170 hom., cov: 32)
  • Exomes 𝑓: 0.022 (809 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.33
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-26476291-C-T is Benign according to our data. Variant chr2-26476291-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 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.2703G>A	p.Ser901Ser	synonymous	Exon 23 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.462G>A	p.Ser154Ser	synonymous	Exon 6 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2703G>A	p.Ser901Ser	synonymous	Exon 23 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.2703G>A	p.Ser901Ser	synonymous	Exon 23 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.462G>A	p.Ser154Ser	synonymous	Exon 6 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.462G>A	p.Ser154Ser	synonymous	Exon 5 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5924 AN: 152096 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0363 AC: 8397 AN: 231158 AF XY: 0.0347

Gnomad AFR exome AF: 0.0712

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.00195

Gnomad EAS exome AF: 0.135

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0260

GnomAD4 exome AF: 0.0216 AC: 31335 AN: 1450570 Hom.: 809 Cov.: 35 AF XY: 0.0221 AC XY: 15927 AN XY: 721932

African (AFR) AF: 0.0694 AC: 2321 AN: 33422

American (AMR) AF: 0.0422 AC: 1882 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26104

East Asian (EAS) AF: 0.135 AC: 5335 AN: 39590

South Asian (SAS) AF: 0.0443 AC: 3814 AN: 86162

European-Finnish (FIN) AF: 0.0340 AC: 1495 AN: 43946

Middle Eastern (MID) AF: 0.0190 AC: 95 AN: 5006

European-Non Finnish (NFE) AF: 0.0131 AC: 14582 AN: 1111590

Other (OTH) AF: 0.0294 AC: 1766 AN: 60126

GnomAD4 genome AF: 0.0390 AC: 5943 AN: 152212 Hom.: 170 Cov.: 32 AF XY: 0.0407 AC XY: 3026 AN XY: 74426

African (AFR) AF: 0.0673 AC: 2795 AN: 41532

American (AMR) AF: 0.0407 AC: 623 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.135 AC: 698 AN: 5164

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4824

European-Finnish (FIN) AF: 0.0419 AC: 445 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 937 AN: 67968

Other (OTH) AF: 0.0322 AC: 68 AN: 2114

Alfa AF: 0.0211 Hom.: 39

Bravo AF: 0.0404

Asia WGS AF: 0.0990 AC: 340 AN: 3462

EpiCase AF: 0.0134

EpiControl AF: 0.0132

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.66
CADD	Benign	0.039
DANN	Benign	0.54
PhyloP100		-3.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4997760; hg19: chr2-26699159; COSMIC: COSV55495153; COSMIC: COSV55495153;