Genetic Variant TDP2:c.252-109T>A (chr6-24658843-A-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_016614.3(TDP2):c.252-109T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000078 in 1,103,080 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000368 (56/152208) while in subpopulation AFR AF = 0.00132 (55/41530). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.0000316

AC:

AN:

950872

Hom.:

Cov.:

AF XY:

0.0000250

AC XY:

AN XY:

480656

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

21548

American (AMR)

AF:

0.00

AC:

AN:

26970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17756

East Asian (EAS)

AF:

0.00

AC:

AN:

34494

South Asian (SAS)

AF:

0.00

AC:

AN:

59382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4320

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

704222

Other (OTH)

AF:

0.000117

AC:

AN:

42620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000368

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67992

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

7045

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.4

(source)

DANN

Benign

0.79

PhyloP100

0.26

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