NM_016614.3:c.252-2549A>G

Variant names:

• chr6-24661283-T-C
• rs2056999
• NM_016614.3:c.252-2549A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016614.3(TDP2):​c.252-2549A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 152,152 control chromosomes in the GnomAD database, including 45,540 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.77 (45540 hom., cov: 31)
• Consequence: TDP2 NM_016614.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.858
• Publications: 8 publications found

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]

TDP2 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 23

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP2	NM_016614.3	c.252-2549A>G		intron_variant	Intron 2 of 6	ENST00000378198.9	NP_057698.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP2	ENST00000378198.9	c.252-2549A>G		intron_variant	Intron 2 of 6	1	NM_016614.3	ENSP00000367440.4
TDP2	ENST00000341060.3	c.78-2549A>G		intron_variant	Intron 1 of 5	1		ENSP00000345345.3
TDP2	ENST00000478507.1	n.319+5243A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116620 AN: 152034 Hom.: 45477 Cov.: 31

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.741

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.767 AC: 116743 AN: 152152 Hom.: 45540 Cov.: 31 AF XY: 0.763 AC XY: 56746 AN XY: 74374

African (AFR) AF: 0.907 AC: 37674 AN: 41538

American (AMR) AF: 0.799 AC: 12200 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2421 AN: 3470

East Asian (EAS) AF: 0.855 AC: 4423 AN: 5176

South Asian (SAS) AF: 0.718 AC: 3466 AN: 4826

European-Finnish (FIN) AF: 0.631 AC: 6652 AN: 10548

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.696 AC: 47291 AN: 67994

Other (OTH) AF: 0.744 AC: 1575 AN: 2116

Alfa AF: 0.752 Hom.: 7983

Bravo AF: 0.790

Asia WGS AF: 0.792 AC: 2752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.92
DANN	Benign	0.51
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2056999; hg19: chr6-24661511;