X-16689565-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_175859.3(CTPS2):c.757G>A(p.Val253Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,208,152 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000012 ( 0 hom. 4 hem. )

Consequence

CTPS2
NM_175859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 7.57

Variant links:

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]

CTPS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTPS2	NM_175859.3 link	c.757G>A	p.Val253Ile	missense_variant	Exon 8 of 19	ENST00000359276.9	NP_787055.1	Q9NRF8A0A024RC00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTPS2	ENST00000359276.9 link	c.757G>A	p.Val253Ile	missense_variant	Exon 8 of 19	1	NM_175859.3	ENSP00000352222.4	Q9NRF8
CTPS2	ENST00000380241.7 link	c.757G>A	p.Val253Ile	missense_variant	Exon 8 of 19	1		ENSP00000369590.3	Q9NRF8
CTPS2	ENST00000443824.5 link	c.757G>A	p.Val253Ile	missense_variant	Exon 8 of 19	2		ENSP00000401264.1	Q9NRF8

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33964

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000962

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

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

GnomAD3 exomes

AF:

0.0000220

AC:

AN:

182015

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66481

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000371

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1096358

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

361740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000199

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33964

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000962

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000279

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.757G>A (p.V253I) alteration is located in exon 8 (coding exon 7) of the CTPS2 gene. This alteration results from a G to A substitution at nucleotide position 757, causing the valine (V) at amino acid position 253 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Laterality defects, autosomal dominant

Uncertain:1

Shanghai Key Laboratory of Birth Defects, Children's Hospital of Fudan University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;.

M_CAP

Benign

0.066

MetaRNN

Benign

0.42

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.98

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.42

MutPred

0.63

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.55

MPC

1.7

ClinPred

0.51

GERP RS

5.8

Varity_R

0.36

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: -16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over