6-24651092-C-T

Variant names:

• chr6-24651092-C-T
• rs3181245
• NM_016614.3:c.808-23G>A

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.808-23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,332 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: 26)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TDP2 NM_016614.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78
• Publications: 0 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=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP2	NM_016614.3	c.808-23G>A		intron_variant	Intron 6 of 6	ENST00000378198.9	NP_057698.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP2	ENST00000378198.9	c.808-23G>A		intron_variant	Intron 6 of 6	1	NM_016614.3	ENSP00000367440.4
TDP2	ENST00000341060.3	c.634-23G>A		intron_variant	Intron 5 of 5	1		ENSP00000345345.3
TDP2	ENST00000478507.1	n.491-23G>A		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422332 Hom.: 0 Cov.: 27 AF XY: 0.00000142 AC XY: 1 AN XY: 706522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32416

American (AMR) AF: 0.00 AC: 0 AN: 41924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39194

South Asian (SAS) AF: 0.00 AC: 0 AN: 83170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085786

Other (OTH) AF: 0.00 AC: 0 AN: 58898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.46
PhyloP100		-1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3181245; hg19: chr6-24651320;