2-26457866-G-A

Variant names:

• chr2-26457866-G-A
• rs56025829
• NM_194248.3:c.*372C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):​c.*372C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 664,794 control chromosomes in the GnomAD database, including 496 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 (353 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (143 hom.)
• Consequence: OTOF NM_194248.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.598

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-26457866-G-A is Benign according to our data. Variant chr2-26457866-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 335426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.*372C>T		3_prime_UTR_variant	Exon 47 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.*174C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371	c.*372C>T		3_prime_UTR_variant	Exon 47 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598	c.*174C>T		3_prime_UTR_variant	Exon 29 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5850 AN: 151918 Hom.: 353 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.00614 AC: 3148 AN: 512758 Hom.: 143 Cov.: 6 AF XY: 0.00525 AC XY: 1423 AN XY: 271250

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.000213

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000432

Gnomad4 FIN exome AF: 0.000999

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0386 AC: 5862 AN: 152036 Hom.: 353 Cov.: 32 AF XY: 0.0364 AC XY: 2705 AN XY: 74330

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0205

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.00489 Hom.: 4

Bravo AF: 0.0441

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs56025829; hg19: chr2-26680734; COSMIC: COSV55503401; COSMIC: COSV55503401;