6-24665966-G-C

Variant names:

• chr6-24665966-G-C
• rs3756815
• NM_016614.3:c.251+560C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016614.3(TDP2):​c.251+560C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0789 in 1,046,456 control chromosomes in the GnomAD database, including 7,598 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 0.13 (2252 hom., cov: 32)
  • Exomes 𝑓: 0.071 (5346 hom.)
• Consequence: TDP2 NM_016614.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.252
• Publications: 4 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP2	NM_016614.3	MANE Select	c.251+560C>G		intron	N/A	NP_057698.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP2	ENST00000378198.9	TSL:1 MANE Select	c.251+560C>G		intron	N/A	ENSP00000367440.4
	TDP2	ENST00000341060.3	TSL:1	c.77+153C>G		intron	N/A	ENSP00000345345.3
	TDP2	ENST00000478507.1	TSL:5	n.319+560C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19284 AN: 151926 Hom.: 2241 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: 0.0154

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0707 AC: 63227 AN: 894410 Hom.: 5346 Cov.: 12 AF XY: 0.0706 AC XY: 30825 AN XY: 436650

African (AFR) AF: 0.222 AC: 4318 AN: 19408

American (AMR) AF: 0.284 AC: 3535 AN: 12458

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 664 AN: 14694

East Asian (EAS) AF: 0.445 AC: 12423 AN: 27938

South Asian (SAS) AF: 0.119 AC: 3911 AN: 32910

European-Finnish (FIN) AF: 0.0132 AC: 341 AN: 25766

Middle Eastern (MID) AF: 0.0629 AC: 217 AN: 3450

European-Non Finnish (NFE) AF: 0.0473 AC: 34033 AN: 719252

Other (OTH) AF: 0.0982 AC: 3785 AN: 38534

GnomAD4 genome AF: 0.127 AC: 19328 AN: 152046 Hom.: 2252 Cov.: 32 AF XY: 0.130 AC XY: 9696 AN XY: 74334

African (AFR) AF: 0.216 AC: 8953 AN: 41430

American (AMR) AF: 0.256 AC: 3904 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 163 AN: 3470

East Asian (EAS) AF: 0.449 AC: 2312 AN: 5144

South Asian (SAS) AF: 0.143 AC: 691 AN: 4822

European-Finnish (FIN) AF: 0.0154 AC: 163 AN: 10592

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.0418 AC: 2840 AN: 67996

Other (OTH) AF: 0.130 AC: 274 AN: 2112

Alfa AF: 0.0760 Hom.: 137

Bravo AF: 0.151

Asia WGS AF: 0.271 AC: 944 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.35
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3756815; hg19: chr6-24666194;