X-16698965-T-C

Variant names:

• chrX-16698965-T-C
• rs752670958
• NM_175859.3:c.295A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175859.3(CTPS2):​c.295A>G​(p.Asn99Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000919 in 1,088,150 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N99H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24117377).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175859.3. 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
	CTPS2	NM_175859.3	MANE Select	c.295A>G	p.Asn99Asp	missense	Exon 3 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.295A>G	p.Asn99Asp	missense	Exon 3 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.295A>G	p.Asn99Asp	missense	Exon 3 of 19	NP_062831.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS2	ENST00000359276.9	TSL:1 MANE Select	c.295A>G	p.Asn99Asp	missense	Exon 3 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.295A>G	p.Asn99Asp	missense	Exon 3 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000944988.1		c.295A>G	p.Asn99Asp	missense	Exon 3 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000584 AC: 1 AN: 171308 AF XY: 0.0000175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

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: 9.19e-7 AC: 1 AN: 1088150 Hom.: 0 Cov.: 27 AF XY: 0.00000282 AC XY: 1 AN XY: 354686

African (AFR) AF: 0.00 AC: 0 AN: 26013

American (AMR) AF: 0.0000297 AC: 1 AN: 33691

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19228

East Asian (EAS) AF: 0.00 AC: 0 AN: 29894

South Asian (SAS) AF: 0.00 AC: 0 AN: 51595

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40477

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837377

Other (OTH) AF: 0.00 AC: 0 AN: 45758

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.71	N
PhyloP100		6.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.047
Sift	Benign	0.22	T
Sift4G	Benign	0.24	T
Polyphen		0.0050	B
Vest4		0.24
MutPred		0.33		Gain of ubiquitination at K100 (P = 0.0438)
MVP		0.40
MPC		1.4
ClinPred		0.66	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.94
Mutation Taster		=88/12	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: rs752670958; hg19: chrX-16717088;