chr6-24658560-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_StrongPM2PP3_StrongPP5
The NM_016614.3(TDP2):c.425+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000841 in 1,604,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000089 ( 0 hom. )
Consequence
TDP2
NM_016614.3 splice_donor
NM_016614.3 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.88
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 Pathogenic. Variant got 11 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.15886134 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.1, offset of -20, new splice context is: gggGTgtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 6-24658560-C-T is Pathogenic according to our data. Variant chr6-24658560-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 226424.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-24658560-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TDP2 | NM_016614.3 | c.425+1G>A | splice_donor_variant | ENST00000378198.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TDP2 | ENST00000378198.9 | c.425+1G>A | splice_donor_variant | 1 | NM_016614.3 | P1 | |||
TDP2 | ENST00000341060.3 | c.251+1G>A | splice_donor_variant | 1 | |||||
TDP2 | ENST00000478285.1 | n.612+1G>A | splice_donor_variant, non_coding_transcript_variant | 2 | |||||
TDP2 | ENST00000478507.1 | n.320-5407G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152138Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000613 AC: 15AN: 244864Hom.: 0 AF XY: 0.0000529 AC XY: 7AN XY: 132412
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GnomAD4 exome AF: 0.0000888 AC: 129AN: 1452552Hom.: 0 Cov.: 30 AF XY: 0.0000914 AC XY: 66AN XY: 722450
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74328
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Spinocerebellar ataxia, autosomal recessive 23 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 23, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at