rs200569046

Variant names:

• chr2-210656592-T-C
• rs200569046
• NM_001875.5:c.3626T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001875.5(CPS1):​c.3626T>C​(p.Met1209Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,612,688 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1209V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00021 (4 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 7.52
• Publications: 8 publications found

Genes affected

CPS1 (HGNC:2323): (carbamoyl-phosphate synthase 1) The mitochondrial enzyme encoded by this gene catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate. This reaction is the first committed step of the urea cycle, which is important in the removal of excess urea from cells. The encoded protein may also represent a core mitochondrial nucleoid protein. Three transcript variants encoding different isoforms have been found for this gene. The shortest isoform may not be localized to the mitochondrion. Mutations in this gene have been associated with carbamoyl phosphate synthetase deficiency, susceptibility to persistent pulmonary hypertension, and susceptibility to venoocclusive disease after bone marrow transplantation.[provided by RefSeq, May 2010]

CPS1 Gene-Disease associations (from GenCC):

• carbamoyl phosphate synthetase I deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001875.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.014570594).
• BP6: Variant 2-210656592-T-C is Benign according to our data. Variant chr2-210656592-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210758.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000212 (32/150840) while in subpopulation EAS AF = 0.0039 (20/5124). AF 95% confidence interval is 0.00259. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. 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
	CPS1	NM_001875.5	MANE Select	c.3626T>C	p.Met1209Thr	missense	Exon 30 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.3659T>C	p.Met1220Thr	missense	Exon 31 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.3626T>C	p.Met1209Thr	missense	Exon 31 of 39	NP_001116105.2	P31327-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.3626T>C	p.Met1209Thr	missense	Exon 30 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.3644T>C	p.Met1215Thr	missense	Exon 31 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.2273T>C	p.Met758Thr	missense	Exon 20 of 28	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes AF: 0.000212 AC: 32 AN: 150732 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000488

GnomAD2 exomes AF: 0.000545 AC: 137 AN: 251476 AF XY: 0.000508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00576

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1461848 Hom.: 4 Cov.: 35 AF XY: 0.000201 AC XY: 146 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00602 AC: 239 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.000768 AC: 41 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111972

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000212 AC: 32 AN: 150840 Hom.: 0 Cov.: 28 AF XY: 0.000272 AC XY: 20 AN XY: 73580

African (AFR) AF: 0.00 AC: 0 AN: 41004

American (AMR) AF: 0.00 AC: 0 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00390 AC: 20 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00107 AC: 11 AN: 10290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67856

Other (OTH) AF: 0.000483 AC: 1 AN: 2070

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000227

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Congenital hyperammonemia, type I (4)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	0.0093	T
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	-0.14	N
PhyloP100		7.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.27	B
Vest4		0.80
MVP		0.93
MPC		0.28
ClinPred		0.20	T
GERP RS		5.9
Varity_R		0.81
gMVP		0.88
Mutation Taster		=78/22	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: rs200569046; hg19: chr2-211521316;