6-24654405-TACTC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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	UniProt
TDP2	NM_016614.3	c.636+3_636+6del		splice_donor_5th_base_variant, intron_variant		ENST00000378198.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP2	ENST00000378198.9	c.636+3_636+6del		splice_donor_5th_base_variant, intron_variant		1	NM_016614.3	P1
TDP2	ENST00000341060.3	c.462+3_462+6del		splice_donor_5th_base_variant, intron_variant		1
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 Cov.: 33

GnomAD4 exome AF: 0.0000106 AC: 12 AN: 1127058 Hom.: 0 AF XY: 0.0000193 AC XY: 11 AN XY: 571316

Gnomad4 AFR exome AF: 0.0000412

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000463

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.0000286

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000827

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1240335250; hg19: chr6-24654633;