6-24654405-TACTC-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_016614.3(TDP2):c.636+3_636+6del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000106 in 1,127,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
TDP2
NM_016614.3 splice_donor_5th_base, intron
NM_016614.3 splice_donor_5th_base, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.40
Genes affected
TDP2 (HGNC:17768): (tyrosyl-DNA phosphodiesterase 2) This gene encodes a member of a superfamily of divalent cation-dependent phosphodiesterases. The encoded protein associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation. This protein has sequence and structural similarities with APE1 endonuclease, which is involved in both DNA repair and the activation of transcription factors. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 6-24654405-TACTC-T is Pathogenic according to our data. Variant chr6-24654405-TACTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 812705.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-24654405-TACTC-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TDP2 | NM_016614.3 | c.636+3_636+6del | splice_donor_5th_base_variant, intron_variant | ENST00000378198.9 | NP_057698.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TDP2 | ENST00000378198.9 | c.636+3_636+6del | splice_donor_5th_base_variant, intron_variant | 1 | NM_016614.3 | ENSP00000367440 | P1 | |||
| TDP2 | ENST00000341060.3 | c.462+3_462+6del | splice_donor_5th_base_variant, intron_variant | 1 | ENSP00000345345 | |||||
| TDP2 | ENST00000478285.1 | n.826_829del | non_coding_transcript_exon_variant | 3/3 | 2 | |||||
| TDP2 | ENST00000478507.1 | n.320-1256_320-1253del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.0000106 AC: 12AN: 1127058Hom.: 0 AF XY: 0.0000193 AC XY: 11AN XY: 571316
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GnomAD4 genome
GnomAD4 genome
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33
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cerebellar ataxia Pathogenic:1
| Pathogenic, criteria provided, single submitter | in vitro;research | Molecular Medicine, University of Pavia | Jan 28, 2020 | According to the ACMG 2015 guidelines, the variant in classified as "pathogenic". The variant is not reported in frequency databases GnomAD and TOPMed. The variant was heterozygous in parents and unaffected family members, while homozygous in both affected siblings with same phenotype. The variant causes exon skipping and nonsense-mediated mRNA decay, according to both in silico predictions and functional assays. Furthermore, it induces absence of protein expression and decreased repair of TOP2-induced double strand breaks in the DNA. Other LOF (splice-site) variants have been reported in the gene in previous studies (DOI: 10.1212/NXG.0000000000000262, and 10.1038/ng.2929). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 7
Find out detailed SpliceAI scores and Pangolin per-transcript scores at