chr2-26479605-C-T

Position:

• chr2-26479605-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_194248.3(OTOF):​c.1961G>A​(p.Arg654Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,612,422 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.05

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0053245723).
• BP6: Variant 2-26479605-C-T is Benign according to our data. Variant chr2-26479605-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48181.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.1961G>A	p.Arg654Gln	missense_variant	17/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.1961G>A	p.Arg654Gln	missense_variant	17/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.1961G>A	p.Arg654Gln	missense_variant	17/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.1961G>A	p.Arg654Gln	missense_variant	17/46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152098 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00486

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000626 AC: 156 AN: 249244 Hom.: 0 AF XY: 0.000554 AC XY: 75 AN XY: 135498

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00654

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000394 AC: 575 AN: 1460206 Hom.: 1 Cov.: 34 AF XY: 0.000373 AC XY: 271 AN XY: 726300

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00451

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.000313

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152216 Hom.: 0 Cov.: 34 AF XY: 0.000269 AC XY: 20 AN XY: 74420

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00487

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000496 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000570 AC: 69

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	This variant is associated with the following publications: (PMID: 31095577) -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 21, 2016

p.Arg654Gln in exon 17 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (48/8588) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs184605839). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.059	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.94	N;N
REVEL	Benign	0.20
Sift	Benign	0.25	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0010	B;.
Vest4		0.20
MVP		0.63
MPC		0.18
ClinPred		0.031	T
GERP RS		2.8
Varity_R		0.057
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs184605839; hg19: chr2-26702473;