chrX-16683156-C-T

Variant names:

• chrX-16683156-C-T
• rs148995160
• NM_175859.3:c.943G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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. 16/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.827
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 2208255.
• BS2: High Hemizygotes in GnomAd4 at 15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS2	NM_175859.3	MANE Select	c.943G>A	p.Ala315Thr	missense	Exon 9 of 19	NP_787055.1	Q9NRF8
	CTPS2	NM_001144002.2		c.943G>A	p.Ala315Thr	missense	Exon 9 of 19	NP_001137474.1	Q9NRF8
	CTPS2	NM_019857.5		c.943G>A	p.Ala315Thr	missense	Exon 9 of 19	NP_062831.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTPS2	ENST00000359276.9	TSL:1 MANE Select	c.943G>A	p.Ala315Thr	missense	Exon 9 of 19	ENSP00000352222.4	Q9NRF8
	CTPS2	ENST00000380241.7	TSL:1	c.943G>A	p.Ala315Thr	missense	Exon 9 of 19	ENSP00000369590.3	Q9NRF8
	CTPS2	ENST00000944988.1		c.943G>A	p.Ala315Thr	missense	Exon 9 of 19	ENSP00000615047.1

Frequencies

GnomAD3 genomes AF: 0.000484 AC: 54 AN: 111594 Hom.: 0 Cov.: 22

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

GnomAD2 exomes AF: 0.000529 AC: 97 AN: 183485 AF XY: 0.000486

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 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.: 0 Cov.: 29 AF XY: 0.000720 AC XY: 261 AN XY: 362425

African (AFR) AF: 0.000227 AC: 6 AN: 26383

American (AMR) AF: 0.000227 AC: 8 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54130

European-Finnish (FIN) AF: 0.0000493 AC: 2 AN: 40528

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4130

European-Non Finnish (NFE) AF: 0.000994 AC: 836 AN: 841046

Other (OTH) AF: 0.000521 AC: 24 AN: 46058

GnomAD4 genome AF: 0.000484 AC: 54 AN: 111594 Hom.: 0 Cov.: 22 AF XY: 0.000444 AC XY: 15 AN XY: 33788

African (AFR) AF: 0.000130 AC: 4 AN: 30737

American (AMR) AF: 0.000193 AC: 2 AN: 10362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000865 AC: 46 AN: 53172

Other (OTH) AF: 0.00134 AC: 2 AN: 1497

Alfa AF: 0.000715 Hom.: 33

Bravo AF: 0.000468

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.3
DANN	Benign	0.97
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.099	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.83
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.049	D
Polyphen		0.086	B
Vest4		0.074
MVP		0.82
MPC		0.80
ClinPred		0.011	T
GERP RS		3.1
Varity_R		0.23
gMVP		0.65
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs148995160; hg19: chrX-16701279; COSMIC: COSV100827037;