6-24657736-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016614.3(TDP2):​c.517+76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 644,306 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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>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.517+76A>G		intron	N/A	ENSP00000367440.4
	TDP2	ENST00000341060.3	TSL:1	c.343+76A>G		intron	N/A	ENSP00000345345.3
	TDP2	ENST00000478285.1	TSL:2	n.704+76A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000310 AC: 2 AN: 644306 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 337290

African (AFR) AF: 0.00 AC: 0 AN: 14684

American (AMR) AF: 0.00 AC: 0 AN: 18590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15180

East Asian (EAS) AF: 0.00 AC: 0 AN: 29730

South Asian (SAS) AF: 0.00 AC: 0 AN: 49074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2838

European-Non Finnish (NFE) AF: 0.00000456 AC: 2 AN: 438844

Other (OTH) AF: 0.00 AC: 0 AN: 30588

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 8321

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0030
DANN	Benign	0.70
PhyloP100		-2.1

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;