6-24651160-G-T

Variant names:

• chr6-24651160-G-T
• rs3181244
• NM_016614.3:c.808-91C>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.808-91C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000112 in 892,568 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: 0.0000011 (0 hom.)
• Consequence: TDP2 NM_016614.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.975
• 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=-0.9).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP2	NM_016614.3	MANE Select	c.808-91C>A		intron	N/A	NP_057698.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP2	ENST00000378198.9	TSL:1 MANE Select	c.808-91C>A		intron	N/A	ENSP00000367440.4
	TDP2	ENST00000341060.3	TSL:1	c.634-91C>A		intron	N/A	ENSP00000345345.3
	TDP2	ENST00000874524.1		c.802-91C>A		intron	N/A	ENSP00000544583.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000112 AC: 1 AN: 892568 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 450806

⚠️ 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: 20774

American (AMR) AF: 0.00 AC: 0 AN: 21574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16774

East Asian (EAS) AF: 0.00 AC: 0 AN: 35234

South Asian (SAS) AF: 0.00 AC: 0 AN: 55484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3054

European-Non Finnish (NFE) AF: 0.00000151 AC: 1 AN: 663550

Other (OTH) AF: 0.00 AC: 0 AN: 40636

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.60
PhyloP100		-0.97

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: rs3181244; hg19: chr6-24651388;