NM_175859.3:c.1039G>A

Variant names:

• chrX-16678417-C-T
• rs756391001
• NM_175859.3:c.1039G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_175859.3(CTPS2):​c.1039G>A​(p.Glu347Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,199,195 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000017 (0 hom. 1 hem.)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65
• 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=0.05702281).

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.1039G>A	p.Glu347Lys	missense	Exon 10 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.1039G>A	p.Glu347Lys	missense	Exon 10 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.1039G>A	p.Glu347Lys	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.1039G>A	p.Glu347Lys	missense	Exon 10 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.1039G>A	p.Glu347Lys	missense	Exon 10 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000944988.1		c.1039G>A	p.Glu347Lys	missense	Exon 10 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111534 Hom.: 0 Cov.: 22

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: 0.0000564

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000229 AC: 4 AN: 174983 AF XY: 0.00

Gnomad AFR exome AF: 0.0000793

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000390

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000175 AC: 19 AN: 1087661 Hom.: 0 Cov.: 27 AF XY: 0.00000283 AC XY: 1 AN XY: 353751

African (AFR) AF: 0.0000381 AC: 1 AN: 26225

American (AMR) AF: 0.00 AC: 0 AN: 35013

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19216

East Asian (EAS) AF: 0.00 AC: 0 AN: 30151

South Asian (SAS) AF: 0.00 AC: 0 AN: 53209

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.0000216 AC: 18 AN: 833602

Other (OTH) AF: 0.00 AC: 0 AN: 45749

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111534 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33708

African (AFR) AF: 0.00 AC: 0 AN: 30658

American (AMR) AF: 0.00 AC: 0 AN: 10404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5999

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

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53176

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.8
DANN	Benign	0.19
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.25	N
PhyloP100		1.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.058
Sift	Benign	1.0	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.41		Gain of ubiquitination at E347 (P = 0.0192)
MVP		0.21
MPC		0.92
ClinPred		0.016	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.17
gMVP		0.68
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: rs756391001; hg19: chrX-16696540;