chrX-16683156-C-A

Variant names:

• chrX-16683156-C-A
• rs148995160
• NM_175859.3:c.943G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_175859.3(CTPS2):​c.943G>T​(p.Ala315Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,594 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. 14/21 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. A315T) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.827
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37666932).

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.943G>T	p.Ala315Ser	missense	Exon 9 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.943G>T	p.Ala315Ser	missense	Exon 9 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.943G>T	p.Ala315Ser	missense	Exon 9 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.943G>T	p.Ala315Ser	missense	Exon 9 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.943G>T	p.Ala315Ser	missense	Exon 9 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000944988.1		c.943G>T	p.Ala315Ser	missense	Exon 9 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111594 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000651

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111594 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33788

African (AFR) AF: 0.0000651 AC: 2 AN: 30737

American (AMR) AF: 0.00 AC: 0 AN: 10362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53172

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

Alfa AF: 0.00 Hom.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	6.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.83
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.098	B
Vest4		0.24
MutPred		0.45		Gain of sheet (P = 0.0221)
MVP		0.74
MPC		0.81
ClinPred		0.59	D
GERP RS		3.1
Varity_R		0.32
gMVP		0.66
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: rs148995160; hg19: chrX-16701279;