chr2-210675762-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. 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: Benign; risk factor no assertion criteria provided B:1 O:1
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19932953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.4196A>C	p.Asn1399Thr	missense_variant	Exon 36 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.4196A>C	p.Asn1399Thr	missense_variant	Exon 36 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

CARBAMOYL PHOSPHATE SYNTHETASE I POLYMORPHISM Benign:1

Sep 01, 2011

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pulmonary hypertension, neonatal, susceptibility to Other:1

Sep 01, 2011

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.74	.;N;.
PhyloP100		3.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.28
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.43
MutPred		0.24		.;Gain of glycosylation at N1399 (P = 0.0571);.;
MVP		0.73
MPC		0.24
ClinPred		0.25	T
GERP RS		6.1
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

Other links and lift over

dbSNP: rs121912594; hg19: chr2-211540486;