X-16639228-C-T

Variant names:

• chrX-16639228-C-T
• rs1931923433
• NM_175859.3:c.1312G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_175859.3(CTPS2):​c.1312G>A​(p.Glu438Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000367 in 1,089,927 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

Genes affected

CTPS2 (HGNC:2520): (CTP synthase 2) The protein encoded by this gene catalyzes the formation of CTP from UTP with the concomitant deamination of glutamine to glutamate. This protein is the rate-limiting enzyme in the synthesis of cytosine nucleotides, which play an important role in various metabolic processes and provide the precursors necessary for the synthesis of RNA and DNA. Cancer cells that exhibit increased cell proliferation also exhibit an increased activity of this encoded protein. Thus, this protein is an attractive target for selective chemotherapy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTPS2	NM_175859.3	c.1312G>A	p.Glu438Lys	missense_variant	Exon 14 of 19	ENST00000359276.9	NP_787055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTPS2	ENST00000359276.9	c.1312G>A	p.Glu438Lys	missense_variant	Exon 14 of 19	1	NM_175859.3	ENSP00000352222.4
CTPS2	ENST00000380241.7	c.1312G>A	p.Glu438Lys	missense_variant	Exon 14 of 19	1		ENSP00000369590.3
CTPS2	ENST00000443824.5	c.1312G>A	p.Glu438Lys	missense_variant	Exon 14 of 19	2		ENSP00000401264.1
CTPS2	ENST00000455276.1	c.175G>A	p.Glu59Lys	missense_variant	Exon 4 of 5	5		ENSP00000400431.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000367 AC: 4 AN: 1089927 Hom.: 0 Cov.: 28 AF XY: 0.00000281 AC XY: 1 AN XY: 355529

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: 0.00000479

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1312G>A (p.E438K) alteration is located in exon 14 (coding exon 13) of the CTPS2 gene. This alteration results from a G to A substitution at nucleotide position 1312, causing the glutamic acid (E) at amino acid position 438 to be replaced by a lysine (K). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;.;.
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.9	H;H;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.69
MutPred		0.53		Gain of methylation at E438 (P = 0.0074);Gain of methylation at E438 (P = 0.0074);Gain of methylation at E438 (P = 0.0074);
MVP		0.65
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1931923433; hg19: chrX-16657351; COSMIC: COSV100826893;