chr2-210605129-G-A

Position:

• chr2-210605129-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001875.5(CPS1):​c.1864G>A​(p.Val622Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain ATP-grasp 1 (size 192) in uniprot entity CPSM_HUMAN there are 43 pathogenic changes around while only 0 benign (100%) in NM_001875.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5	c.1864G>A	p.Val622Met	missense_variant	17/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.1864G>A	p.Val622Met	missense_variant	17/38	1	NM_001875.5	ENSP00000233072	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460000 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This missense change has been observed in individual(s) with clinical features of carbamoyl phosphate synthetase I deficiency (PMID: 21120950). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 556372). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 622 of the CPS1 protein (p.Val622Met). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.94
MutPred		0.78		.;Loss of sheet (P = 0.0817);.;
MVP		0.94
MPC		0.78
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.85
gMVP		0.90

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

Other links and lift over

dbSNP: rs1553512962; hg19: chr2-211469853;