2-26492641-T-C

Variant names:

• chr2-26492641-T-C
• rs4665856
• NM_194248.3:c.897+2301A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_194248.3(OTOF):​c.897+2301A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 151,916 control chromosomes in the GnomAD database, including 17,895 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.47 (17895 hom., cov: 32)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 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.897+2301A>G		intron	N/A	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.897+2301A>G		intron	N/A	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.897+2301A>G		intron	N/A	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.897+2301A>G		intron	N/A	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71382 AN: 151798 Hom.: 17865 Cov.: 32

Gnomad AFR AF: 0.548

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.906

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.413

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.470 AC: 71474 AN: 151916 Hom.: 17895 Cov.: 32 AF XY: 0.479 AC XY: 35596 AN XY: 74246

African (AFR) AF: 0.548 AC: 22691 AN: 41384

American (AMR) AF: 0.403 AC: 6154 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1298 AN: 3472

East Asian (EAS) AF: 0.906 AC: 4680 AN: 5166

South Asian (SAS) AF: 0.547 AC: 2630 AN: 4804

European-Finnish (FIN) AF: 0.588 AC: 6206 AN: 10552

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.388 AC: 26349 AN: 67952

Other (OTH) AF: 0.419 AC: 882 AN: 2104

Alfa AF: 0.414 Hom.: 7600

Bravo AF: 0.460

Asia WGS AF: 0.727 AC: 2523 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.41
DANN	Benign	0.35
PhyloP100		-0.42
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4665856;

hg19: chr2-26715509;