chr2-26495076-G-A

Variant names:

• chr2-26495076-G-A
• rs55886964
• NM_194248.3:c.766-3C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):​c.766-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,613,976 control chromosomes in the GnomAD database, including 1,120 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (64 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1056 hom.)
• Consequence: OTOF NM_194248.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002061
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.41
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-26495076-G-A is Benign according to our data. Variant chr2-26495076-G-A is described in ClinVar as Benign. ClinVar VariationId is 48274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0259 (3943/152246) while in subpopulation SAS AF = 0.0435 (210/4830). AF 95% confidence interval is 0.0387. There are 64 homozygotes in GnomAd4. There are 1953 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AR gene

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.766-3C>T		splice_region intron	N/A	NP_919224.1
	OTOF	NM_001287489.2		c.766-3C>T		splice_region 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.766-3C>T		splice_region intron	N/A	ENSP00000272371.2
	OTOF	ENST00000403946.7	TSL:5	c.766-3C>T		splice_region intron	N/A	ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3941 AN: 152128 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0428

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0313 AC: 7842 AN: 250788 AF XY: 0.0339

Gnomad AFR exome AF: 0.00536

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.0372

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0349 AC: 51026 AN: 1461730 Hom.: 1056 Cov.: 33 AF XY: 0.0357 AC XY: 25978 AN XY: 727196

African (AFR) AF: 0.00436 AC: 146 AN: 33480

American (AMR) AF: 0.0109 AC: 488 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 711 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0507 AC: 4373 AN: 86258

European-Finnish (FIN) AF: 0.0553 AC: 2952 AN: 53340

Middle Eastern (MID) AF: 0.0241 AC: 139 AN: 5766

European-Non Finnish (NFE) AF: 0.0363 AC: 40339 AN: 1111936

Other (OTH) AF: 0.0310 AC: 1872 AN: 60392

GnomAD4 genome AF: 0.0259 AC: 3943 AN: 152246 Hom.: 64 Cov.: 32 AF XY: 0.0262 AC XY: 1953 AN XY: 74438

African (AFR) AF: 0.00611 AC: 254 AN: 41554

American (AMR) AF: 0.0133 AC: 204 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5158

South Asian (SAS) AF: 0.0435 AC: 210 AN: 4830

European-Finnish (FIN) AF: 0.0522 AC: 554 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0370 AC: 2518 AN: 67998

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0321 Hom.: 36

Bravo AF: 0.0215

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.0352

EpiControl AF: 0.0330

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.0040
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: rs55886964; hg19: chr2-26717944;