rs143596142

Variant names:

• chr6-24650833-A-C
• rs143596142
• NM_016614.3:c.1044T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-24650833-A-C
• chr6-24650833-A-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_016614.3(TDP2):​c.1044T>G​(p.Pro348Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000874 in 1,614,136 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (4 hom.)
• Consequence: TDP2 NM_016614.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.54
• Publications: 1 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-24650833-A-C is Benign according to our data. Variant chr6-24650833-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2656287.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000971 (148/152344) while in subpopulation AMR AF = 0.00118 (18/15302). AF 95% confidence interval is 0.000852. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.1044T>G	p.Pro348Pro	synonymous	Exon 7 of 7	NP_057698.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP2	ENST00000378198.9	TSL:1 MANE Select	c.1044T>G	p.Pro348Pro	synonymous	Exon 7 of 7	ENSP00000367440.4	O95551-1
	TDP2	ENST00000341060.3	TSL:1	c.870T>G	p.Pro290Pro	synonymous	Exon 6 of 6	ENSP00000345345.3	X6R5A3
	TDP2	ENST00000874524.1		c.1038T>G	p.Pro346Pro	synonymous	Exon 7 of 7	ENSP00000544583.1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00103 AC: 259 AN: 251420 AF XY: 0.00103

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000862

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000864 AC: 1263 AN: 1461792 Hom.: 4 Cov.: 32 AF XY: 0.000868 AC XY: 631 AN XY: 727206

African (AFR) AF: 0.00266 AC: 89 AN: 33480

American (AMR) AF: 0.00136 AC: 61 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 71 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86256

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53404

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.000775 AC: 862 AN: 1111952

Other (OTH) AF: 0.00131 AC: 79 AN: 60392

GnomAD4 genome AF: 0.000971 AC: 148 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000966 AC XY: 72 AN XY: 74508

African (AFR) AF: 0.00111 AC: 46 AN: 41586

American (AMR) AF: 0.00118 AC: 18 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00130 Hom.: 2

Bravo AF: 0.00127

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.7
DANN	Benign	0.68
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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: rs143596142; hg19: chr6-24651061;