chr2-210675762-A-C

Variant names:

• chr2-210675762-A-C
• rs121912594
• NM_001875.5:c.4196A>C
• CPS1 p.Asn1399Thr

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001875.5(CPS1):​c.4196A>C​(p.Asn1399Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N1399N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• Publications: 1 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: Myriad Women's Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001875.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19932953).

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.4196A>C	p.Asn1399Thr	missense	Exon 36 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.4229A>C	p.Asn1410Thr	missense	Exon 37 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.4196A>C	p.Asn1399Thr	missense	Exon 37 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.4196A>C	p.Asn1399Thr	missense	Exon 36 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.4214A>C	p.Asn1405Thr	missense	Exon 37 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.2843A>C	p.Asn948Thr	missense	Exon 26 of 28	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.26
Eigen_PC	Benign	0.00056
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.74	N
PhyloP100		3.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	0.92	T
Varity_R		0.56
gMVP		0.62
Mutation Taster		=43/57	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121912594;

hg19: chr2-211540486;