chr20-3796541-C-T

Variant names:

• chr20-3796541-C-T
• rs926222369
• NM_021873.4:c.10C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021873.4(CDC25B):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CDC25B NM_021873.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.836
• Publications: 0 publications found

Genes affected

CDC25B (HGNC:1726): (cell division cycle 25B) CDC25B is a member of the CDC25 family of phosphatases. CDC25B activates the cyclin dependent kinase CDC2 by removing two phosphate groups and it is required for entry into mitosis. CDC25B shuttles between the nucleus and the cytoplasm due to nuclear localization and nuclear export signals. The protein is nuclear in the M and G1 phases of the cell cycle and moves to the cytoplasm during S and G2. CDC25B has oncogenic properties, although its role in tumor formation has not been determined. Multiple transcript variants for this gene exist. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06769043).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021873.4. 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
	CDC25B	NM_021873.4	MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 16	NP_068659.1	P30305-1
	CDC25B	NM_004358.5		c.10C>T	p.Pro4Ser	missense	Exon 1 of 16	NP_004349.1	P30305-2
	CDC25B	NM_021872.4		c.10C>T	p.Pro4Ser	missense	Exon 1 of 15	NP_068658.1	P30305-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC25B	ENST00000245960.10	TSL:1 MANE Select	c.10C>T	p.Pro4Ser	missense	Exon 1 of 16	ENSP00000245960.5	P30305-1
	CDC25B	ENST00000439880.6	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 1 of 16	ENSP00000405972.2	P30305-2
	CDC25B	ENST00000340833.4	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 1 of 15	ENSP00000339170.4	P30305-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000117 AC: 1 AN: 85532 AF XY: 0.0000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000556

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: 7.50e-7 AC: 1 AN: 1333022 Hom.: 0 Cov.: 35 AF XY: 0.00000152 AC XY: 1 AN XY: 656542

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26594

American (AMR) AF: 0.0000349 AC: 1 AN: 28674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22768

East Asian (EAS) AF: 0.00 AC: 0 AN: 29904

South Asian (SAS) AF: 0.00 AC: 0 AN: 73432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3908

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057120

Other (OTH) AF: 0.00 AC: 0 AN: 55408

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.84
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.038
Sift	Benign	0.040	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.36	B
Vest4		0.064
MutPred		0.13		Gain of phosphorylation at P4 (P = 0.0185)
MVP		0.20
MPC		0.26
ClinPred		0.20	T
GERP RS		2.3
PromoterAI		-0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.40
Mutation Taster		=94/6	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: rs926222369; hg19: chr20-3777188;