NM_175859.3:c.784A>G

Variant names:

• chrX-16689538-T-C
• rs758782939
• NM_175859.3:c.784A>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.784A>G​(p.Ile262Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,096,321 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• 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=0.072633624).

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.784A>G	p.Ile262Val	missense	Exon 8 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.784A>G	p.Ile262Val	missense	Exon 8 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.784A>G	p.Ile262Val	missense	Exon 8 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.784A>G	p.Ile262Val	missense	Exon 8 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.784A>G	p.Ile262Val	missense	Exon 8 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000944988.1		c.784A>G	p.Ile262Val	missense	Exon 8 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 181992 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1096321 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 361701

African (AFR) AF: 0.00 AC: 0 AN: 26359

American (AMR) AF: 0.00 AC: 0 AN: 35136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.00 AC: 0 AN: 53861

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840774

Other (OTH) AF: 0.0000217 AC: 1 AN: 46024

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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	0.061
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.76
DANN	Benign	0.18
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.070
Sift	Benign	0.74	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.63		Gain of helix (P = 0.0325)
MVP		0.35
MPC		0.69
ClinPred		0.019	T
GERP RS		-2.4
Varity_R		0.051
gMVP		0.77
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs758782939; hg19: chrX-16707661;