rs760895692

Variant names:

• chr2-210594544-G-A
• rs760895692
• NM_001875.5:c.1201G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-210594544-G-A
• chr2-210594544-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PS1_Moderate PM2 BP4

The NM_001875.5(CPS1):​c.1201G>A​(p.Gly401Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.65
• Publications: 6 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS1: Transcript NM_001875.5 (CPS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34321064).

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.1201G>A	p.Gly401Arg	missense	Exon 12 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.1234G>A	p.Gly412Arg	missense	Exon 13 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.1201G>A	p.Gly401Arg	missense	Exon 13 of 39	NP_001116105.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.1201G>A	p.Gly401Arg	missense	Exon 12 of 38	ENSP00000233072.5
	CPS1	ENST00000430249.7	TSL:1	c.1219G>A	p.Gly407Arg	missense	Exon 13 of 39	ENSP00000402608.2
	CPS1	ENST00000451903.3	TSL:1	c.-153G>A		5_prime_UTR	Exon 2 of 28	ENSP00000406136.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151808 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74126

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67882

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	-0.87	N
PhyloP100		8.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.55
Sift	Benign	0.17	T
Sift4G	Benign	0.29	T
Polyphen		0.12	B
Vest4		0.49
MutPred		0.40		Gain of MoRF binding (P = 0.0435)
MVP		0.95
MPC		0.62
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.31
gMVP		0.79
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760895692; hg19: chr2-211459268;