5-138290671-T-C

Position:

• chr5-138290671-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001790.5(CDC25C):​c.832A>G​(p.Asn278Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,459,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CDC25C NM_001790.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029447079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC25C	NM_001790.5	c.832A>G	p.Asn278Asp	missense_variant	9/14	ENST00000323760.11	NP_001781.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC25C	ENST00000323760.11	c.832A>G	p.Asn278Asp	missense_variant	9/14	1	NM_001790.5	ENSP00000321656.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1459258 Hom.: 0 Cov.: 28 AF XY: 0.0000124 AC XY: 9 AN XY: 726136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.832A>G (p.N278D) alteration is located in exon 9 (coding exon 8) of the CDC25C gene. This alteration results from a A to G substitution at nucleotide position 832, causing the asparagine (N) at amino acid position 278 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.26
DEOGEN2	Benign	0.10	T;.;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.25	.;T;.;T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.31	N;.;.;N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.2	N;N;N;N;N
REVEL	Benign	0.032
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.95	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.042
MutPred		0.25		Gain of sheet (P = 0.0125);.;.;Gain of sheet (P = 0.0125);.;
MVP		0.22
MPC		0.19
ClinPred		0.026	T
GERP RS		1.5
Varity_R		0.033
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs970861923; hg19: chr5-137626360;