6-24665112-A-C

Variant names:

• chr6-24665112-A-C
• rs3756819
• NM_016614.3:c.251+1414T>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+1414T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,180 control chromosomes in the GnomAD database, including 2,027 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 0.16 (2027 hom., cov: 32)
• Consequence: TDP2 NM_016614.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.611
• Publications: 9 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.251 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+1414T>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+1414T>G		intron	N/A	ENSP00000367440.4
	TDP2	ENST00000341060.3	TSL:1	c.77+1007T>G		intron	N/A	ENSP00000345345.3
	TDP2	ENST00000478507.1	TSL:5	n.319+1414T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24045 AN: 152062 Hom.: 2027 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.163

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 24039 AN: 152180 Hom.: 2027 Cov.: 32 AF XY: 0.156 AC XY: 11633 AN XY: 74400

African (AFR) AF: 0.178 AC: 7377 AN: 41520

American (AMR) AF: 0.127 AC: 1935 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3468

East Asian (EAS) AF: 0.169 AC: 877 AN: 5186

South Asian (SAS) AF: 0.263 AC: 1267 AN: 4824

European-Finnish (FIN) AF: 0.116 AC: 1225 AN: 10602

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10079 AN: 67996

Other (OTH) AF: 0.161 AC: 340 AN: 2108

Alfa AF: 0.154 Hom.: 3301

Bravo AF: 0.159

Asia WGS AF: 0.221 AC: 769 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.0
DANN	Benign	0.52
PhyloP100		0.61
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: rs3756819; hg19: chr6-24665340;