chr3-25598336-C-T

Variant names:

• chr3-25598336-C-T
• rs764335718
• NM_001330700.2:c.4852G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330700.2(TOP2B):​c.4852G>A​(p.Asp1618Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1618E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TOP2B NM_001330700.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38

Genes affected

TOP2B (HGNC:11990): (DNA topoisomerase II beta) This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, beta, is localized to chromosome 3 and the alpha form is localized to chromosome 17. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1697549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP2B	NM_001330700.2	c.4852G>A	p.Asp1618Asn	missense_variant	Exon 36 of 36	ENST00000264331.9	NP_001317629.1
TOP2B	NM_001068.3	c.4837G>A	p.Asp1613Asn	missense_variant	Exon 36 of 36		NP_001059.2
TOP2B	XM_011534057.4	c.4741G>A	p.Asp1581Asn	missense_variant	Exon 35 of 35		XP_011532359.1
TOP2B	XM_047448821.1	c.4726G>A	p.Asp1576Asn	missense_variant	Exon 35 of 35		XP_047304777.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP2B	ENST00000264331.9	c.4852G>A	p.Asp1618Asn	missense_variant	Exon 36 of 36	5	NM_001330700.2	ENSP00000264331.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245880 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455648 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.087
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.071
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.48	P;B
Vest4		0.24
MutPred		0.19		Gain of glycosylation at S1613 (P = 0.0068);.;
MVP		0.49
MPC		0.049
ClinPred		0.40	T
GERP RS		4.4
Varity_R		0.080
gMVP		0.11

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: rs764335718; hg19: chr3-25639827;