6-24654215-C-T

Variant names:

• chr6-24654215-C-T
• rs3181238
• NM_016614.3:c.636+197G>A

Variant summary

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

The NM_016614.3(TDP2):​c.636+197G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 151,966 control chromosomes in the GnomAD database, including 31,484 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 0.64 (31484 hom., cov: 33)
• Consequence: TDP2 NM_016614.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.731
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP2	NM_016614.3	c.636+197G>A		intron_variant	Intron 5 of 6	ENST00000378198.9	NP_057698.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP2	ENST00000378198.9	c.636+197G>A		intron_variant	Intron 5 of 6	1	NM_016614.3	ENSP00000367440.4
TDP2	ENST00000341060.3	c.462+197G>A		intron_variant	Intron 4 of 5	1		ENSP00000345345.3
TDP2	ENST00000478507.1	n.320-1062G>A		intron_variant	Intron 2 of 3	5
TDP2	ENST00000478285.1	n.*163G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97169 AN: 151848 Hom.: 31451 Cov.: 33

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.811

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.640 AC: 97249 AN: 151966 Hom.: 31484 Cov.: 33 AF XY: 0.632 AC XY: 46960 AN XY: 74264

African (AFR) AF: 0.691 AC: 28629 AN: 41460

American (AMR) AF: 0.544 AC: 8298 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2254 AN: 3464

East Asian (EAS) AF: 0.405 AC: 2093 AN: 5164

South Asian (SAS) AF: 0.576 AC: 2775 AN: 4818

European-Finnish (FIN) AF: 0.618 AC: 6499 AN: 10524

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44450 AN: 67960

Other (OTH) AF: 0.617 AC: 1300 AN: 2106

Alfa AF: 0.611 Hom.: 4340

Bravo AF: 0.638

Asia WGS AF: 0.518 AC: 1788 AN: 3454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.53
PhyloP100		-0.73
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: rs3181238; hg19: chr6-24654443;