Genetic Variant NM_175859.3:c.1312G>A (chrX-16639228-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_175859.3(CTPS2):c.1312G>A(p.Glu438Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000367 in 1,089,927 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

CTPS2
NM_175859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175859.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTPS2	NM_175859.3	MANE Select	c.1312G>A	p.Glu438Lys	missense	Exon 14 of 19	NP_787055.1	Q9NRF8
CTPS2	NM_001144002.2		c.1312G>A	p.Glu438Lys	missense	Exon 14 of 19	NP_001137474.1	Q9NRF8
CTPS2	NM_019857.5		c.1312G>A	p.Glu438Lys	missense	Exon 14 of 19	NP_062831.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTPS2	ENST00000359276.9	TSL:1 MANE Select	c.1312G>A	p.Glu438Lys	missense	Exon 14 of 19	ENSP00000352222.4	Q9NRF8
CTPS2	ENST00000380241.7	TSL:1	c.1312G>A	p.Glu438Lys	missense	Exon 14 of 19	ENSP00000369590.3	Q9NRF8
CTPS2	ENST00000443824.5	TSL:2	c.1312G>A	p.Glu438Lys	missense	Exon 14 of 19	ENSP00000401264.1	Q9NRF8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000367

AC:

AN:

1089927

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

355529

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26244

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19326

East Asian (EAS)

AF:

0.00

AC:

AN:

30180

South Asian (SAS)

AF:

0.00

AC:

AN:

53926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.00000479

AC:

AN:

834594

Other (OTH)

AF:

0.00

AC:

AN:

45823

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.9

PhyloP100

6.1

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.69

MutPred

0.53

Gain of methylation at E438 (P = 0.0074)

MVP

0.65

MPC

2.0

ClinPred

1.0

GERP RS

5.5

Varity_R

0.86

gMVP

0.94

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over