2-26516408-T-C

Variant names:

• chr2-26516408-T-C
• rs76712142
• NM_194248.3:c.509+10A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):​c.509+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00658 in 1,612,670 control chromosomes in the GnomAD database, including 620 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 (303 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (317 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.37
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-26516408-T-C is Benign according to our data. Variant chr2-26516408-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 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.509+10A>G		intron	N/A	NP_919224.1
	OTOF	NM_001287489.2		c.509+10A>G		intron	N/A	NP_001274418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.509+10A>G		intron	N/A	ENSP00000272371.2
	OTOF	ENST00000403946.7	TSL:5	c.509+10A>G		intron	N/A	ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5273 AN: 152146 Hom.: 302 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0248

GnomAD2 exomes AF: 0.00900 AC: 2254 AN: 250352 AF XY: 0.00634

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00611

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000530

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00365 AC: 5335 AN: 1460406 Hom.: 317 Cov.: 33 AF XY: 0.00305 AC XY: 2218 AN XY: 726374

African (AFR) AF: 0.126 AC: 4206 AN: 33422

American (AMR) AF: 0.00694 AC: 310 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00521 AC: 30 AN: 5754

European-Non Finnish (NFE) AF: 0.000268 AC: 298 AN: 1111042

Other (OTH) AF: 0.00772 AC: 466 AN: 60338

GnomAD4 genome AF: 0.0347 AC: 5283 AN: 152264 Hom.: 303 Cov.: 32 AF XY: 0.0336 AC XY: 2498 AN XY: 74448

African (AFR) AF: 0.118 AC: 4896 AN: 41520

American (AMR) AF: 0.0192 AC: 294 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68020

Other (OTH) AF: 0.0246 AC: 52 AN: 2116

Alfa AF: 0.0153 Hom.: 25

Bravo AF: 0.0399

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.40
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs76712142; hg19: chr2-26739276;