X-16683156-C-T

Position:

chrX-16683156-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_175859.3(CTPS2):c.943G>A(p.Ala315Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,208,645 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 276 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., 15 hem., cov: 22)

Exomes 𝑓: 0.00080 ( 0 hom. 261 hem. )

Consequence

CTPS2
NM_175859.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.827

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09860152).

BP6

Variant X-16683156-C-T is Benign according to our data. Variant chrX-16683156-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2208255.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAd4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTPS2	NM_175859.3 linkuse as main transcript	c.943G>A	p.Ala315Thr	missense_variant	9/19	ENST00000359276.9	NP_787055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CTPS2	ENST00000359276.9 linkuse as main transcript	c.943G>A	p.Ala315Thr	missense_variant	9/19	1	NM_175859.3	ENSP00000352222	P1
CTPS2	ENST00000380241.7 linkuse as main transcript	c.943G>A	p.Ala315Thr	missense_variant	9/19	1		ENSP00000369590	P1
CTPS2	ENST00000443824.5 linkuse as main transcript	c.943G>A	p.Ala315Thr	missense_variant	9/19	2		ENSP00000401264	P1

Frequencies

GnomAD3 genomes

AF:

0.000484

AC:

AN:

111594

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

33788

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000193

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:

0.000865

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.000529

AC:

AN:

183485

Hom.:

AF XY:

0.000486

AC XY:

AN XY:

67919

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000801

AC:

879

AN:

1097051

Hom.:

Cov.:

AF XY:

0.000720

AC XY:

261

AN XY:

362425

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.0000493

Gnomad4 NFE exome

AF:

0.000994

Gnomad4 OTH exome

AF:

0.000521

GnomAD4 genome

AF:

0.000484

AC:

AN:

111594

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

33788

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.000193

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000865

Gnomad4 OTH

AF:

0.00134

Alfa

AF:

0.000758

Hom.:

Bravo

AF:

0.000468

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2024

The c.943G>A (p.A315T) alteration is located in exon 9 (coding exon 8) of the CTPS2 gene. This alteration results from a G to A substitution at nucleotide position 943, causing the alanine (A) at amino acid position 315 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

CTPS2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

6.3

DANN

Benign

0.97

DEOGEN2

Uncertain

0.67

D;D;D

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.85

T;.;.

M_CAP

Benign

0.079

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.98

L;L;L

MutationTaster

Benign

0.63

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.024

D;D;D

Sift4G

Uncertain

0.049

D;D;D

Polyphen

0.086

B;B;B

Vest4

0.074

MVP

0.82

MPC

0.80

ClinPred

0.011

GERP RS

3.1

Varity_R

0.23

gMVP

0.65

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

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