X-16590804-C-T

Variant names:

• chrX-16590804-C-T
• rs770159997
• NM_175859.3:c.1750G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_175859.3(CTPS2):​c.1750G>A​(p.Glu584Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000738 in 1,084,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000074 (0 hom. 4 hem.)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062794715).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

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.1750G>A	p.Glu584Lys	missense	Exon 18 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.1750G>A	p.Glu584Lys	missense	Exon 18 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.1750G>A	p.Glu584Lys	missense	Exon 18 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.1750G>A	p.Glu584Lys	missense	Exon 18 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.1750G>A	p.Glu584Lys	missense	Exon 18 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000483053.1	TSL:1	n.242G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180882 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: 0.0000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000738 AC: 8 AN: 1084046 Hom.: 0 Cov.: 26 AF XY: 0.0000114 AC XY: 4 AN XY: 350782

African (AFR) AF: 0.00 AC: 0 AN: 26155

American (AMR) AF: 0.00 AC: 0 AN: 35105

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19251

East Asian (EAS) AF: 0.00 AC: 0 AN: 30101

South Asian (SAS) AF: 0.00 AC: 0 AN: 53575

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00000844 AC: 7 AN: 829714

Other (OTH) AF: 0.0000219 AC: 1 AN: 45625

GnomAD4 genome Cov.: 23

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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.15
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.090
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.25		Gain of ubiquitination at E584 (P = 0.0045)
MVP		0.23
MPC		0.92
ClinPred		0.13	T
GERP RS		4.2
Varity_R		0.13
gMVP		0.82
Mutation Taster		=96/4	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: rs770159997; hg19: chrX-16608927;