6-24657736-T-G

Variant names:

• chr6-24657736-T-G
• rs3212231
• NM_016614.3:c.517+76A>C

Variant summary

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

The NM_016614.3(TDP2):​c.517+76A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 793,824 control chromosomes in the GnomAD database, including 79,982 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 0.39 (12711 hom., cov: 32)
  • Exomes 𝑓: 0.45 (67271 hom.)
• Consequence: TDP2 NM_016614.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 8 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.492 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.517+76A>C		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.517+76A>C		intron	N/A	ENSP00000367440.4
	TDP2	ENST00000341060.3	TSL:1	c.343+76A>C		intron	N/A	ENSP00000345345.3
	TDP2	ENST00000478285.1	TSL:2	n.704+76A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59604 AN: 151906 Hom.: 12714 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.446 AC: 286081 AN: 641800 Hom.: 67271 AF XY: 0.441 AC XY: 148241 AN XY: 336020

African (AFR) AF: 0.221 AC: 3236 AN: 14634

American (AMR) AF: 0.317 AC: 5868 AN: 18520

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 6738 AN: 15124

East Asian (EAS) AF: 0.186 AC: 5505 AN: 29674

South Asian (SAS) AF: 0.305 AC: 14939 AN: 48916

European-Finnish (FIN) AF: 0.499 AC: 22289 AN: 44670

Middle Eastern (MID) AF: 0.431 AC: 1219 AN: 2828

European-Non Finnish (NFE) AF: 0.488 AC: 213181 AN: 436962

Other (OTH) AF: 0.430 AC: 13106 AN: 30472

GnomAD4 genome AF: 0.392 AC: 59626 AN: 152024 Hom.: 12711 Cov.: 32 AF XY: 0.388 AC XY: 28848 AN XY: 74304

African (AFR) AF: 0.240 AC: 9939 AN: 41484

American (AMR) AF: 0.353 AC: 5389 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1546 AN: 3470

East Asian (EAS) AF: 0.199 AC: 1030 AN: 5184

South Asian (SAS) AF: 0.286 AC: 1376 AN: 4818

European-Finnish (FIN) AF: 0.496 AC: 5220 AN: 10534

Middle Eastern (MID) AF: 0.441 AC: 128 AN: 290

European-Non Finnish (NFE) AF: 0.497 AC: 33758 AN: 67942

Other (OTH) AF: 0.367 AC: 776 AN: 2112

Alfa AF: 0.450 Hom.: 8321

Bravo AF: 0.377

Asia WGS AF: 0.242 AC: 835 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0020
DANN	Benign	0.75
PhyloP100		-2.1
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: rs3212231; hg19: chr6-24657964; COSMIC: COSV61968735;