chrX-16689454-C-A

Position:

• chrX-16689454-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_175859.3(CTPS2):​c.868G>T​(p.Asp290Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTPS2	NM_175859.3	c.868G>T	p.Asp290Tyr	missense_variant	8/19	ENST00000359276.9	NP_787055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTPS2	ENST00000359276.9	c.868G>T	p.Asp290Tyr	missense_variant	8/19	1	NM_175859.3	ENSP00000352222.4
CTPS2	ENST00000380241.7	c.868G>T	p.Asp290Tyr	missense_variant	8/19	1		ENSP00000369590.3
CTPS2	ENST00000443824.5	c.868G>T	p.Asp290Tyr	missense_variant	8/19	2		ENSP00000401264.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

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

Apr 12, 2022

The c.868G>T (p.D290Y) alteration is located in exon 8 (coding exon 7) of the CTPS2 gene. This alteration results from a G to T substitution at nucleotide position 868, causing the aspartic acid (D) at amino acid position 290 to be replaced by a tyrosine (Y). 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	0.19
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;.;.
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.26	B;B;B
Vest4		0.52
MutPred		0.30		Gain of MoRF binding (P = 0.0572);Gain of MoRF binding (P = 0.0572);Gain of MoRF binding (P = 0.0572);
MVP		0.62
MPC		1.9
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.63
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1923514111; hg19: chrX-16707577;