chr3-25598318-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330700.2(TOP2B):c.4870A>G(p.Met1624Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,608,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TOP2B
NM_001330700.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.47

Publications

0 publications found

Variant links:

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

TOP2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.4870A>G	p.Met1624Val	missense	Exon 36 of 36	NP_001317629.1	Q02880-1
	TOP2B	NM_001068.3		c.4855A>G	p.Met1619Val	missense	Exon 36 of 36	NP_001059.2	Q59H80

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOP2B	ENST00000264331.9	TSL:5 MANE Select	c.4870A>G	p.Met1624Val	missense	Exon 36 of 36	ENSP00000264331.4	Q02880-1
TOP2B	ENST00000435706.7	TSL:1	c.4855A>G	p.Met1619Val	missense	Exon 36 of 36	ENSP00000396704.2
TOP2B	ENST00000424225.2	TSL:1	c.4771A>G	p.Met1591Val	missense	Exon 36 of 36	ENSP00000391112.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1456480

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723980

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

44044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26010

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

85150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109118

Other (OTH)

AF:

0.00

AC:

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

TOP2B-related neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.073

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.8

PhyloP100

6.5

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.60

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Benign

0.66

Polyphen

0.86

Vest4

0.80

MutPred

0.33

Gain of sheet (P = 0.0043)

MVP

0.45

MPC

0.052

ClinPred

0.73

GERP RS

5.9

Varity_R

0.70

gMVP

0.34

Mutation Taster

=80/20

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over