dbSNP rs141143406: CTPS2:p.Val201Ala (chrX-16693178-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_175859.3(CTPS2):c.602T>C(p.Val201Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,208,049 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 0.000018 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Consequence

CTPS2
NM_175859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.70

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

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.602T>C	p.Val201Ala	missense	Exon 6 of 19	NP_787055.1	Q9NRF8
CTPS2	NM_001144002.2		c.602T>C	p.Val201Ala	missense	Exon 6 of 19	NP_001137474.1	Q9NRF8
CTPS2	NM_019857.5		c.602T>C	p.Val201Ala	missense	Exon 6 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.602T>C	p.Val201Ala	missense	Exon 6 of 19	ENSP00000352222.4	Q9NRF8
CTPS2	ENST00000380241.7	TSL:1	c.602T>C	p.Val201Ala	missense	Exon 6 of 19	ENSP00000369590.3	Q9NRF8
CTPS2	ENST00000944988.1		c.602T>C	p.Val201Ala	missense	Exon 6 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110482

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000195

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

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183239

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000273

AC:

AN:

1097567

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363049

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26392

American (AMR)

AF:

0.0000284

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841529

Other (OTH)

AF:

0.0000434

AC:

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

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

AF:

0.0000181

AC:

AN:

110482

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

32750

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30376

American (AMR)

AF:

0.000195

AC:

AN:

10258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3510

South Asian (SAS)

AF:

0.00

AC:

AN:

2584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52853

Other (OTH)

AF:

0.00

AC:

AN:

1484

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

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

0.71

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

0.18

MutationAssessor

Pathogenic

3.3

PhyloP100

8.7

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.82

MVP

0.59

MPC

2.1

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.99

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over