6-24650833-A-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_016614.3(TDP2):c.1044T>G(p.Pro348=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 2656287.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-24650833-A-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDP2	NM_016614.3	c.1044T>G	p.Pro348=	synonymous_variant	7/7	ENST00000378198.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP2	ENST00000378198.9	c.1044T>G	p.Pro348=	synonymous_variant	7/7	1	NM_016614.3	P1
TDP2	ENST00000341060.3	c.870T>G	p.Pro290=	synonymous_variant	6/6	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

GnomAD3 exomes AF: 0.00103 AC: 259 AN: 251420 Hom.: 3 AF XY: 0.00103 AC XY: 140 AN XY: 135888

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 SAS exome AF: 0.000882

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

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000775

Gnomad4 OTH exome AF: 0.00131

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

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00331

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

TDP2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.7
Dann	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs143596142; hg19: chr6-24651061;