2-26477188-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_194248.3(OTOF):c.2507G>A(p.Arg836His) variant causes a missense change. The variant allele was found at a frequency of 0.0000553 in 1,610,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R836R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
OTOF
NM_194248.3 missense
NM_194248.3 missense
Scores
5
8
4
Clinical Significance
Conservation
PhyloP100: 5.87
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-26477188-C-T is Benign according to our data. Variant chr2-26477188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178510.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTOF | NM_194248.3 | c.2507G>A | p.Arg836His | missense_variant | 21/47 | ENST00000272371.7 | |
OTOF | NM_194323.3 | c.266G>A | p.Arg89His | missense_variant | 4/29 | ENST00000339598.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTOF | ENST00000272371.7 | c.2507G>A | p.Arg836His | missense_variant | 21/47 | 1 | NM_194248.3 | A1 | |
OTOF | ENST00000339598.8 | c.266G>A | p.Arg89His | missense_variant | 4/29 | 1 | NM_194323.3 |
Frequencies
GnomAD3 genomes AF: 0.000302 AC: 46AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000696 AC: 17AN: 244158Hom.: 0 AF XY: 0.0000676 AC XY: 9AN XY: 133162
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GnomAD4 exome AF: 0.0000295 AC: 43AN: 1458288Hom.: 0 Cov.: 33 AF XY: 0.0000290 AC XY: 21AN XY: 725318
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GnomAD4 genome AF: 0.000302 AC: 46AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 27, 2014 | The p.Arg836His variant in OTOF has not been previously reported in individuals with hearing loss, but has been identified in 0.01% (1/8583) of European America n chromosomes and 0.02% (1/4367) of African American chromosomes by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200670445). A lthough this variant has been seen in the general population, its frequency is n ot high enough to rule out a pathogenic role. The Arginine (Arg) at position 836 is highly conserved in mammals and evolutionary distant species, raising the po ssibility that a change at this position may not be tolerated. However, addition al computational prediction tools do not provide strong support for or against a n impact to the protein. In summary, the clinical significance of the p.Arg836Hi s variant is uncertain. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;D;D;.
REVEL
Pathogenic
Sift
Benign
T;T;.;T;T;.
Sift4G
Benign
T;T;.;T;T;.
Polyphen
P;D;.;D;.;D
Vest4
MVP
MPC
0.56
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at