dbSNP rs2294689: TDP2:p.Gln249Glu (chr6-24653045-G-C) – 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.745C>G(p.Gln249Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 1,613,784 control chromosomes in the GnomAD database, including 12,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 2259 hom., cov: 32)

Exomes 𝑓: 0.077 ( 10737 hom. )

Consequence

TDP2
NM_016614.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.07

Publications

27 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039203465).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP2	NM_016614.3 link	c.745C>G	p.Gln249Glu	missense_variant	Exon 6 of 7	ENST00000378198.9	NP_057698.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TDP2	ENST00000378198.9 link	c.745C>G	p.Gln249Glu	missense_variant	Exon 6 of 7	1	NM_016614.3	ENSP00000367440.4
TDP2	ENST00000341060.3 link	c.571C>G	p.Gln191Glu	missense_variant	Exon 5 of 6	1		ENSP00000345345.3
TDP2	ENST00000478507.1 link	n.428C>G		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19295

AN:

151992

Hom.:

2248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.0470

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.0153

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0418

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.139

AC:

34960

AN:

251338

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.223

Gnomad AMR exome

AF:

0.382

Gnomad ASJ exome

AF:

0.0515

Gnomad EAS exome

AF:

0.436

Gnomad FIN exome

AF:

0.0159

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0992

GnomAD4 exome

AF:

0.0774

AC:

113167

AN:

1461674

Hom.:

10737

Cov.:

AF XY:

0.0765

AC XY:

55611

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.227

AC:

7587

AN:

33476

American (AMR)

AF:

0.364

AC:

16268

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0481

AC:

1256

AN:

26134

East Asian (EAS)

AF:

0.442

AC:

17540

AN:

39694

South Asian (SAS)

AF:

0.126

AC:

10836

AN:

86254

European-Finnish (FIN)

AF:

0.0147

AC:

786

AN:

53348

Middle Eastern (MID)

AF:

0.0633

AC:

365

AN:

5768

European-Non Finnish (NFE)

AF:

0.0474

AC:

52713

AN:

1111896

Other (OTH)

AF:

0.0963

AC:

5816

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

5359

10717

16076

21434

26793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2584

5168

7752

10336

12920

<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:

0.127

AC:

19338

AN:

152110

Hom.:

2259

Cov.:

AF XY:

0.131

AC XY:

9711

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.216

AC:

8958

AN:

41474

American (AMR)

AF:

0.256

AC:

3908

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0470

AC:

163

AN:

3468

East Asian (EAS)

AF:

0.450

AC:

2316

AN:

5150

South Asian (SAS)

AF:

0.143

AC:

690

AN:

4826

European-Finnish (FIN)

AF:

0.0153

AC:

162

AN:

10598

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0418

AC:

2839

AN:

67998

Other (OTH)

AF:

0.130

AC:

274

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

776

1553

2329

3106

3882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.0644

Hom.:

600

Bravo

AF:

0.151

TwinsUK

AF:

0.0475

AC:

176

ALSPAC

AF:

0.0566

AC:

218

ESP6500AA

AF:

0.204

AC:

897

ESP6500EA

AF:

0.0443

AC:

381

ExAC

AF:

0.130

AC:

15769

Asia WGS

AF:

0.271

AC:

944

AN:

3478

EpiCase

AF:

0.0412

EpiControl

AF:

0.0440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.045

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

L;.

PhyloP100

3.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.24

Sift

Benign

0.30

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.091

B;.

Vest4

0.11

MPC

0.19

ClinPred

0.011

GERP RS

5.3

Varity_R

0.18

gMVP

0.31

Mutation Taster

=94/6

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