NM_001330700.2:c.4858G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001330700.2(TOP2B):c.4858G>A(p.Val1620Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000742 in 1,609,868 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1620D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

TOP2B
NM_001330700.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.88

Publications

6 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070174336).

BP6

Variant 3-25598330-C-T is Benign according to our data. Variant chr3-25598330-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 999917.

BS2

High AC in GnomAd4 at 184 AD gene.

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.4858G>A	p.Val1620Ile	missense	Exon 36 of 36	NP_001317629.1	Q02880-1
	TOP2B	NM_001068.3		c.4843G>A	p.Val1615Ile	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.4858G>A	p.Val1620Ile	missense	Exon 36 of 36	ENSP00000264331.4	Q02880-1
TOP2B	ENST00000435706.7	TSL:1	c.4843G>A	p.Val1615Ile	missense	Exon 36 of 36	ENSP00000396704.2
TOP2B	ENST00000424225.2	TSL:1	c.4759G>A	p.Val1587Ile	missense	Exon 36 of 36	ENSP00000391112.2

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000752

AC:

185

AN:

246006

AF XY:

0.000652

show subpopulations

Gnomad AFR exome

AF:

0.000713

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.00292

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000812

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.000693

AC:

1010

AN:

1457560

Hom.:

Cov.:

AF XY:

0.000716

AC XY:

519

AN XY:

724692

show subpopulations

African (AFR)

AF:

0.000901

AC:

AN:

33314

American (AMR)

AF:

0.00159

AC:

AN:

44092

Ashkenazi Jewish (ASJ)

AF:

0.00185

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

85240

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000695

AC:

771

AN:

1109970

Other (OTH)

AF:

0.00139

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.00121

AC:

184

AN:

152308

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41568

American (AMR)

AF:

0.00274

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000838

Hom.:

Bravo

AF:

0.00166

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.000609

AC:

ExAC

AF:

0.000604

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000602

EpiControl

AF:

0.000831

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

TOP2B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.066

Eigen

Benign

0.048

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.77

M_CAP

Benign

0.011

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

4.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.0

REVEL

Benign

0.088

Sift

Benign

0.35

Sift4G

Benign

0.42

Polyphen

0.92

Vest4

0.23

MVP

0.42

MPC

0.048

ClinPred

0.046

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.090

Mutation Taster

=98/2

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

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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