3-25607612-A-G

Variant names:

• chr3-25607612-A-G
• rs2067120
• NM_001330700.2:c.4094-237T>C

Variant summary

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

The NM_001330700.2(TOP2B):​c.4094-237T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,148 control chromosomes in the GnomAD database, including 1,869 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 0.15 (1869 hom., cov: 32)
• Consequence: TOP2B NM_001330700.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.529
• Publications: 2 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 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.4094-237T>C		intron	N/A	NP_001317629.1	Q02880-1
	TOP2B	NM_001068.3		c.4079-237T>C		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.4094-237T>C		intron	N/A	ENSP00000264331.4	Q02880-1
	TOP2B	ENST00000435706.7	TSL:1	c.4079-237T>C		intron	N/A	ENSP00000396704.2
	TOP2B	ENST00000424225.2	TSL:1	c.3995-237T>C		intron	N/A	ENSP00000391112.2

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22160 AN: 152030 Hom.: 1867 Cov.: 32

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.146 AC: 22164 AN: 152148 Hom.: 1869 Cov.: 32 AF XY: 0.148 AC XY: 11007 AN XY: 74372

African (AFR) AF: 0.0620 AC: 2575 AN: 41532

American (AMR) AF: 0.166 AC: 2533 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 532 AN: 3466

East Asian (EAS) AF: 0.195 AC: 1009 AN: 5180

South Asian (SAS) AF: 0.178 AC: 857 AN: 4824

European-Finnish (FIN) AF: 0.209 AC: 2216 AN: 10580

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11994 AN: 67980

Other (OTH) AF: 0.122 AC: 257 AN: 2108

Alfa AF: 0.158 Hom.: 950

Bravo AF: 0.138

Asia WGS AF: 0.163 AC: 566 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.2
DANN	Benign	0.73
PhyloP100		0.53
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: rs2067120; hg19: chr3-25649103;