NM_001330700.2:c.4819G>A

Variant names:

• chr3-25598369-C-T
• rs764317223
• NM_001330700.2:c.4819G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001330700.2(TOP2B):​c.4819G>A​(p.Val1607Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,461,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1607L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TOP2B NM_001330700.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14591283).
• BS2: High AC in GnomAdExome4 at 16 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.4819G>A	p.Val1607Ile	missense	Exon 36 of 36	NP_001317629.1	Q02880-1
	TOP2B	NM_001068.3		c.4804G>A	p.Val1602Ile	missense	Exon 36 of 36	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.4819G>A	p.Val1607Ile	missense	Exon 36 of 36	ENSP00000264331.4	Q02880-1
	TOP2B	ENST00000435706.7	TSL:1	c.4804G>A	p.Val1602Ile	missense	Exon 36 of 36	ENSP00000396704.2
	TOP2B	ENST00000424225.2	TSL:1	c.4720G>A	p.Val1574Ile	missense	Exon 36 of 36	ENSP00000391112.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248604 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1461006 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 726744

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111466

Other (OTH) AF: 0.0000166 AC: 1 AN: 60338

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.089
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		6.4
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.13
Sift	Benign	0.88	T
Sift4G	Benign	0.52	T
Polyphen		0.12	B
Vest4		0.49
MutPred		0.53		Gain of glycosylation at Y1609 (P = 0.004)
MVP		0.22
MPC		0.059
ClinPred		0.17	T
GERP RS		5.6
Varity_R		0.052
gMVP		0.16
Mutation Taster		=75/25	polymorphism

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: rs764317223; hg19: chr3-25639860; COSMIC: COSV99979048; COSMIC: COSV99979048;