Variant X-16698991-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_175859.3(CTPS2):c.269C>T(p.Thr90Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000903 in 1,196,181 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000090 ( 0 hom. 40 hem. )

Consequence

CTPS2
NM_175859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

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 Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 40 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTPS2	NM_175859.3 linkuse as main transcript	c.269C>T	p.Thr90Met	missense_variant	3/19	ENST00000359276.9	NP_787055.1	Q9NRF8A0A024RC00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CTPS2	ENST00000359276.9 linkuse as main transcript	c.269C>T	p.Thr90Met	missense_variant	3/19	1	NM_175859.3	ENSP00000352222.4	Q9NRF8
CTPS2	ENST00000380241.7 linkuse as main transcript	c.269C>T	p.Thr90Met	missense_variant	3/19	1		ENSP00000369590.3	Q9NRF8
CTPS2	ENST00000443824.5 linkuse as main transcript	c.269C>T	p.Thr90Met	missense_variant	3/19	2		ENSP00000401264.1	Q9NRF8

Frequencies

GnomAD3 genomes

AF:

0.0000893

AC:

AN:

112031

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34235

show subpopulations

Gnomad AFR

AF:

0.000227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000368

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000152

AC:

AN:

171262

Hom.:

AF XY:

0.000210

AC XY:

AN XY:

57234

show subpopulations

Gnomad AFR exome

AF:

0.000160

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00107

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000764

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000904

AC:

AN:

1084150

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

351162

show subpopulations

Gnomad4 AFR exome

AF:

0.000154

Gnomad4 AMR exome

AF:

0.0000594

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000862

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000527

Gnomad4 OTH exome

AF:

0.0000876

GnomAD4 genome

AF:

0.0000893

AC:

AN:

112031

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34235

show subpopulations

Gnomad4 AFR

AF:

0.000227

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000368

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000222

AC:

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 24, 2024

The c.269C>T (p.T90M) alteration is located in exon 3 (coding exon 2) of the CTPS2 gene. This alteration results from a C to T substitution at nucleotide position 269, causing the threonine (T) at amino acid position 90 to be replaced by a methionine (M). 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

0.53

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;D;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;.

M_CAP

Pathogenic

0.85

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Uncertain

0.098

MutationAssessor

Pathogenic

3.6

H;H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.27

MVP

0.51

MPC

1.9

ClinPred

0.50

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.97

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