Variant X-16639224-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_175859.3(CTPS2):c.1316A>G(p.His439Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000166 in 1,202,575 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

CTPS2
NM_175859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTPS2	NM_175859.3 linkuse as main transcript	c.1316A>G	p.His439Arg	missense_variant	14/19	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.1316A>G	p.His439Arg	missense_variant	14/19	1	NM_175859.3	ENSP00000352222	P1
CTPS2	ENST00000380241.7 linkuse as main transcript	c.1316A>G	p.His439Arg	missense_variant	14/19	1		ENSP00000369590	P1
CTPS2	ENST00000443824.5 linkuse as main transcript	c.1316A>G	p.His439Arg	missense_variant	14/19	2		ENSP00000401264	P1
CTPS2	ENST00000455276.1 linkuse as main transcript	c.182A>G	p.His61Arg	missense_variant	4/5	5		ENSP00000400431

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111970

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34110

show subpopulations

Gnomad AFR

AF:

0.0000325

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

AF:

9.17e-7

AC:

AN:

1090605

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

356207

show subpopulations

Gnomad4 AFR exome

AF:

0.0000381

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111970

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34110

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.1316A>G (p.H439R) alteration is located in exon 14 (coding exon 13) of the CTPS2 gene. This alteration results from a A to G substitution at nucleotide position 1316, causing the histidine (H) at amino acid position 439 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.88

D;D;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;.;.

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.9

L;L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.0

D;D;D

REVEL

Pathogenic

0.69

Sift

Benign

0.35

T;T;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.43

MutPred

0.56

Gain of disorder (P = 0.0677);Gain of disorder (P = 0.0677);Gain of disorder (P = 0.0677);

MVP

0.77

MPC

2.0

ClinPred

0.97

GERP RS

5.5

Varity_R

0.76

gMVP

0.89

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