6-24650958-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016614.3(TDP2):c.919A>G(p.Ile307Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,614,160 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (6 hom.)
• Consequence: TDP2 NM_016614.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.86

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033581257).
• BP6: Variant 6-24650958-T-C is Benign according to our data. Variant chr6-24650958-T-C is described in ClinVar as [Benign]. Clinvar id is 718735.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-24650958-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00318 (484/152306) while in subpopulation AFR AF= 0.0102 (425/41576). AF 95% confidence interval is 0.00942. There are 0 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDP2	NM_016614.3	c.919A>G	p.Ile307Val	missense_variant	7/7	ENST00000378198.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP2	ENST00000378198.9	c.919A>G	p.Ile307Val	missense_variant	7/7	1	NM_016614.3	P1
TDP2	ENST00000341060.3	c.745A>G	p.Ile249Val	missense_variant	6/6	1
TDP2	ENST00000478507.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 482 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00119 AC: 299 AN: 251448 Hom.: 2 AF XY: 0.000942 AC XY: 128 AN XY: 135892

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000562 AC: 822 AN: 1461854 Hom.: 6 Cov.: 32 AF XY: 0.000549 AC XY: 399 AN XY: 727226

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00291 AC XY: 217 AN XY: 74480

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000635 Hom.: 0

Bravo AF: 0.00364

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.087	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.39	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.20
Sift	Benign	0.45	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.014	B;.
Vest4		0.049
MVP		0.79
MPC		0.19
ClinPred		0.014	T
GERP RS		4.9
Varity_R		0.080
gMVP		0.46

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: rs77273535; hg19: chr6-24651186; COSMIC: COSV100593751; COSMIC: COSV100593751;