5-138286119-C-A

Variant names:

• chr5-138286119-C-A
• rs374637684
• NM_001790.5:c.1175G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001790.5(CDC25C):​c.1175G>T​(p.Arg392Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R392H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC25C NM_001790.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.23
• Publications: 0 publications found

Genes affected

CDC25C (HGNC:1727): (cell division cycle 25C) This gene encodes a conserved protein that plays a key role in the regulation of cell division. The encoded protein directs dephosphorylation of cyclin B-bound CDC2 and triggers entry into mitosis. It also suppresses p53-induced growth arrest. Multiple alternatively spliced transcript variants of this gene have been described. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001790.5. 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
	CDC25C	NM_001790.5	MANE Select	c.1175G>T	p.Arg392Leu	missense	Exon 13 of 14	NP_001781.2	P30307-1
	CDC25C	NM_001287583.2		c.1409G>T	p.Arg470Leu	missense	Exon 13 of 14	NP_001274512.1
	CDC25C	NM_001364026.1		c.1346G>T	p.Arg449Leu	missense	Exon 12 of 13	NP_001350955.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC25C	ENST00000323760.11	TSL:1 MANE Select	c.1175G>T	p.Arg392Leu	missense	Exon 13 of 14	ENSP00000321656.6	P30307-1
	CDC25C	ENST00000513970.5	TSL:2	c.1175G>T	p.Arg392Leu	missense	Exon 13 of 14	ENSP00000424795.1	P30307-1
	CDC25C	ENST00000920904.1		c.1175G>T	p.Arg392Leu	missense	Exon 13 of 14	ENSP00000590963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.82		Loss of disorder (P = 0.0467)
MVP		0.71
MPC		0.78
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.75
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs374637684; hg19: chr5-137621808;