X-16617220-A-C

Variant names:

• chrX-16617220-A-C
• NM_175859.3:c.1476T>G

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.1476T>G​(p.Phe492Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CTPS2 NM_175859.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67
• 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=0.12886304).
• BP6: Variant X-16617220-A-C is Benign according to our data. Variant chrX-16617220-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2528372.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.1476T>G	p.Phe492Leu	missense	Exon 16 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.1476T>G	p.Phe492Leu	missense	Exon 16 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.1476T>G	p.Phe492Leu	missense	Exon 16 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.1476T>G	p.Phe492Leu	missense	Exon 16 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.1476T>G	p.Phe492Leu	missense	Exon 16 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000944988.1		c.1563T>G	p.Phe521Leu	missense	Exon 16 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely benign

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	Uncertain	0.55
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.3
DANN	Benign	0.19
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.23	N
PhyloP100		1.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.35
MutPred		0.53		Loss of methylation at K490 (P = 0.0788)
MVP		0.72
MPC		0.95
ClinPred		0.030	T
GERP RS		0.65
Varity_R		0.13
gMVP		0.92
Mutation Taster		=53/47	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

hg19: chrX-16635343;