chr3-25600666-T-C

Variant names:

• chr3-25600666-T-C
• rs7624894
• NM_001330700.2:c.4615+434A>G

Variant summary

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

The NM_001330700.2(TOP2B):​c.4615+434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 152,168 control chromosomes in the GnomAD database, including 4,980 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 0.20 (4980 hom., cov: 32)
• Consequence: TOP2B NM_001330700.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.262
• Publications: 5 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: ClinGen, Illumina, Ambry Genetics, PanelApp Australia
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330700.2. 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
	TOP2B	NM_001330700.2	MANE Select	c.4615+434A>G		intron	N/A	NP_001317629.1	Q02880-1
	TOP2B	NM_001068.3		c.4600+434A>G		intron	N/A	NP_001059.2	Q59H80

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2B	ENST00000264331.9	TSL:5 MANE Select	c.4615+434A>G		intron	N/A	ENSP00000264331.4	Q02880-1
	TOP2B	ENST00000435706.7	TSL:1	c.4600+434A>G		intron	N/A	ENSP00000396704.2
	TOP2B	ENST00000424225.2	TSL:1	c.4516+434A>G		intron	N/A	ENSP00000391112.2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30892 AN: 152050 Hom.: 4963 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0945

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.203 AC: 30951 AN: 152168 Hom.: 4980 Cov.: 32 AF XY: 0.200 AC XY: 14911 AN XY: 74408

African (AFR) AF: 0.452 AC: 18748 AN: 41474

American (AMR) AF: 0.165 AC: 2522 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3472

East Asian (EAS) AF: 0.118 AC: 610 AN: 5186

South Asian (SAS) AF: 0.136 AC: 657 AN: 4826

European-Finnish (FIN) AF: 0.0995 AC: 1055 AN: 10608

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0945 AC: 6425 AN: 68004

Other (OTH) AF: 0.173 AC: 365 AN: 2112

Alfa AF: 0.123 Hom.: 683

Bravo AF: 0.221

Asia WGS AF: 0.159 AC: 552 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.92
DANN	Benign	0.58
PhyloP100		-0.26
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: rs7624894; hg19: chr3-25642157;