rs10510569

Variant names:

• chr3-25626439-G-A
• rs10510569
• NM_001330700.2:c.2224+121C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001330700.2(TOP2B):​c.2224+121C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 523,482 control chromosomes in the GnomAD database, including 382 homozygotes. 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: 𝑓 0.036 (283 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (99 hom.)
• Consequence: TOP2B NM_001330700.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.826
• Publications: 0 publications found

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]

TOP2B Gene-Disease associations (from GenCC):

• B-cell immunodeficiency, distal limb anomalies, and urogenital malformations

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP2B	NM_001330700.2	c.2224+121C>T		intron_variant	Intron 18 of 35	ENST00000264331.9	NP_001317629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP2B	ENST00000264331.9	c.2224+121C>T		intron_variant	Intron 18 of 35	5	NM_001330700.2	ENSP00000264331.4

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5471 AN: 151986 Hom.: 282 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000927

Gnomad OTH AF: 0.0316

GnomAD4 exome AF: 0.00486 AC: 1806 AN: 371376 Hom.: 99 AF XY: 0.00431 AC XY: 838 AN XY: 194592

African (AFR) AF: 0.123 AC: 1026 AN: 8314

American (AMR) AF: 0.0114 AC: 105 AN: 9196

Ashkenazi Jewish (ASJ) AF: 0.00284 AC: 33 AN: 11630

East Asian (EAS) AF: 0.00 AC: 0 AN: 23966

South Asian (SAS) AF: 0.00529 AC: 107 AN: 20242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33838

Middle Eastern (MID) AF: 0.0205 AC: 34 AN: 1660

European-Non Finnish (NFE) AF: 0.000917 AC: 221 AN: 241068

Other (OTH) AF: 0.0130 AC: 280 AN: 21462

GnomAD4 genome AF: 0.0361 AC: 5484 AN: 152106 Hom.: 283 Cov.: 32 AF XY: 0.0348 AC XY: 2586 AN XY: 74396

African (AFR) AF: 0.123 AC: 5102 AN: 41466

American (AMR) AF: 0.0137 AC: 210 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.000927 AC: 63 AN: 67982

Other (OTH) AF: 0.0313 AC: 66 AN: 2110

Alfa AF: 0.0322 Hom.: 20

Bravo AF: 0.0416

Asia WGS AF: 0.00610 AC: 21 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.64
DANN	Benign	0.48
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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: rs10510569; hg19: chr3-25667930;