Genetic Variant TDP2:c.252-109T>C (chr6-24658843-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016614.3(TDP2):c.252-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,101,538 control chromosomes in the GnomAD database, including 14,973 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 0.16 ( 2021 hom., cov: 32)

Exomes 𝑓: 0.16 ( 12952 hom. )

Consequence

TDP2
NM_016614.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.259

Publications

38 publications found

Variant links:

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

TDP2 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP2	NM_016614.3 link	c.252-109T>C		intron_variant	Intron 2 of 6	ENST00000378198.9	NP_057698.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TDP2	ENST00000378198.9 link	c.252-109T>C	intron_variant	Intron 2 of 6	1	NM_016614.3	ENSP00000367440.4	O95551-1
TDP2	ENST00000341060.3 link	c.78-109T>C	intron_variant	Intron 1 of 5	1		ENSP00000345345.3	X6R5A3
TDP2	ENST00000478285.1 link	n.330T>C	non_coding_transcript_exon_variant	Exon 1 of 3	2
TDP2	ENST00000478507.1 link	n.320-5690T>C	intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

24060

AN:

152058

Hom.:

2021

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.169

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.149

Gnomad OTH

AF:

0.164

GnomAD4 exome

AF:

0.163

AC:

154593

AN:

949360

Hom.:

12952

Cov.:

AF XY:

0.166

AC XY:

79523

AN XY:

479890

show subpopulations

African (AFR)

AF:

0.184

AC:

3953

AN:

21524

American (AMR)

AF:

0.106

AC:

2855

AN:

26958

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

2952

AN:

17742

East Asian (EAS)

AF:

0.185

AC:

6388

AN:

34472

South Asian (SAS)

AF:

0.256

AC:

15161

AN:

59300

European-Finnish (FIN)

AF:

0.115

AC:

4565

AN:

39528

Middle Eastern (MID)

AF:

0.242

AC:

1044

AN:

4314

European-Non Finnish (NFE)

AF:

0.157

AC:

110399

AN:

702958

Other (OTH)

AF:

0.171

AC:

7276

AN:

42564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

6238

12476

18713

24951

31189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3554

7108

10662

14216

17770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.158

AC:

24054

AN:

152178

Hom.:

2021

Cov.:

AF XY:

0.156

AC XY:

11645

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.177

AC:

7370

AN:

41522

American (AMR)

AF:

0.127

AC:

1935

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

600

AN:

3472

East Asian (EAS)

AF:

0.170

AC:

880

AN:

5190

South Asian (SAS)

AF:

0.263

AC:

1267

AN:

4822

European-Finnish (FIN)

AF:

0.115

AC:

1222

AN:

10596

Middle Eastern (MID)

AF:

0.260

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.149

AC:

10097

AN:

67984

Other (OTH)

AF:

0.162

AC:

341

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1037

2075

3112

4150

5187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.152

Hom.:

7045

Bravo

AF:

0.159

Asia WGS

AF:

0.221

AC:

770

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.8

(source)

DANN

Benign

0.84

PhyloP100

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over