Genetic Variant TDP2:p.Thr172Arg (chr6-24657814-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016614.3(TDP2):c.515C>G(p.Thr172Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000731 in 1,367,792 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T172I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

TDP2
NM_016614.3 missense, splice_region

Scores

Splicing: ADA: 0.9508

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.05

Publications

0 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

TDP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016614.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP2	NM_016614.3	MANE Select	c.515C>G	p.Thr172Arg	missense splice_region	Exon 4 of 7	NP_057698.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TDP2	ENST00000378198.9	TSL:1 MANE Select	c.515C>G	p.Thr172Arg	missense splice_region	Exon 4 of 7	ENSP00000367440.4	O95551-1
TDP2	ENST00000341060.3	TSL:1	c.341C>G	p.Thr114Arg	missense splice_region	Exon 3 of 6	ENSP00000345345.3	X6R5A3
TDP2	ENST00000874524.1		c.509C>G	p.Thr170Arg	missense splice_region	Exon 4 of 7	ENSP00000544583.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.31e-7

AC:

AN:

1367792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29380

American (AMR)

AF:

0.00

AC:

AN:

31980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24260

East Asian (EAS)

AF:

0.00

AC:

AN:

37528

South Asian (SAS)

AF:

0.00

AC:

AN:

77976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

9.51e-7

AC:

AN:

1051728

Other (OTH)

AF:

0.00

AC:

AN:

56732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

5.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.5

REVEL

Benign

0.15

Sift

Benign

0.15

Sift4G

Benign

0.38

Polyphen

0.075

Vest4

0.63

MutPred

0.42

Gain of sheet (P = 0.1208)

MVP

0.42

MPC

0.33

ClinPred

0.78

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.24

gMVP

0.63

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.61

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: -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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over