NM_175859.3:c.1032G>C

Variant names:

• chrX-16678424-C-G
• rs983238790
• NM_175859.3:c.1032G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_175859.3(CTPS2):​c.1032G>C​(p.Lys344Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,198,558 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.104
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0838604).
• BP6: Variant X-16678424-C-G is Benign according to our data. Variant chrX-16678424-C-G is described in ClinVar as Benign. ClinVar VariationId is 1339648.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1032G>C	p.Lys344Asn	missense	Exon 10 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.1032G>C	p.Lys344Asn	missense	Exon 10 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.1032G>C	p.Lys344Asn	missense	Exon 10 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.1032G>C	p.Lys344Asn	missense	Exon 10 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.1032G>C	p.Lys344Asn	missense	Exon 10 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000944988.1		c.1032G>C	p.Lys344Asn	missense	Exon 10 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111587 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1086971 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353141

African (AFR) AF: 0.00 AC: 0 AN: 26215

American (AMR) AF: 0.00 AC: 0 AN: 35000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19209

East Asian (EAS) AF: 0.00 AC: 0 AN: 30137

South Asian (SAS) AF: 0.00 AC: 0 AN: 53225

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 832977

Other (OTH) AF: 0.00 AC: 0 AN: 45719

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111587 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33751

African (AFR) AF: 0.00 AC: 0 AN: 30673

American (AMR) AF: 0.00 AC: 0 AN: 10396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53196

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CYTIDINE 5-PRIME TRIPHOSPHATE SYNTHETASE 2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.4
DANN	Benign	0.79
DEOGEN2	Uncertain	0.50	D
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.60	N
PhyloP100		-0.10
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.34		Loss of ubiquitination at K344 (P = 0.0077)
MVP		0.73
MPC		0.95
ClinPred		0.032	T
GERP RS		0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.58
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: rs983238790; hg19: chrX-16696547;