X-16617220-A-C

Position:

• chrX-16617220-A-C

Variant summary

Our verdict is Likely benign. Variant got -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. 14/20 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

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

Verdict is Likely_benign. Variant got -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 id is 2528372.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTPS2	NM_175859.3	c.1476T>G	p.Phe492Leu	missense_variant	16/19	ENST00000359276.9	NP_787055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTPS2	ENST00000359276.9	c.1476T>G	p.Phe492Leu	missense_variant	16/19	1	NM_175859.3	ENSP00000352222	P1
CTPS2	ENST00000380241.7	c.1476T>G	p.Phe492Leu	missense_variant	16/19	1		ENSP00000369590	P1
CTPS2	ENST00000443824.5	c.1476T>G	p.Phe492Leu	missense_variant	16/19	2		ENSP00000401264	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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;T;T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.62	T;.;.
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.23	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.90	N;N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.35
MutPred		0.53		Loss of methylation at K490 (P = 0.0788);Loss of methylation at K490 (P = 0.0788);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-16635343;