rs2294689

Positions:

• chr6-24653045-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (2259 hom., cov: 32)
  • Exomes 𝑓: 0.077 (10737 hom.)
• Consequence: TDP2 NM_016614.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TDP2	NM_016614.3	c.745C>G	p.Gln249Glu	missense_variant	6/7	ENST00000378198.9	NP_057698.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDP2	ENST00000378198.9	c.745C>G	p.Gln249Glu	missense_variant	6/7	1	NM_016614.3	ENSP00000367440	P1
TDP2	ENST00000341060.3	c.571C>G	p.Gln191Glu	missense_variant	5/6	1		ENSP00000345345
TDP2	ENST00000478507.1	n.428C>G		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19295 AN: 151992 Hom.: 2248 Cov.: 32

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

GnomAD3 exomes AF: 0.139 AC: 34960 AN: 251338 Hom.: 5387 AF XY: 0.125 AC XY: 16967 AN XY: 135844

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 SAS exome AF: 0.128

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.: 31 AF XY: 0.0765 AC XY: 55611 AN XY: 727154

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.0481

Gnomad4 EAS exome AF: 0.442

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.0474

Gnomad4 OTH exome AF: 0.0963

GnomAD4 genome AF: 0.127 AC: 19338 AN: 152110 Hom.: 2259 Cov.: 32 AF XY: 0.131 AC XY: 9711 AN XY: 74362

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.0470

Gnomad4 EAS AF: 0.450

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0418

Gnomad4 OTH AF: 0.130

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	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.18	P;P;P
PrimateAI	Benign	0.36	T
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	T
GERP RS		5.3
Varity_R		0.18
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs2294689; hg19: chr6-24653273; COSMIC: COSV61966995; COSMIC: COSV61966995;