rs369061090

Positions:

chr2-210606897-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001875.5(CPS1):c.2148T>A(p.Asn716Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,500 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 0.606

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 0.981

PP5

Variant 2-210606897-T-A is Pathogenic according to our data. Variant chr2-210606897-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 280052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210606897-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5 linkuse as main transcript	c.2148T>A	p.Asn716Lys	missense_variant	18/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.2148T>A	p.Asn716Lys	missense_variant	18/38	1	NM_001875.5	ENSP00000233072	P1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250448

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460508

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726630

show subpopulations

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:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Pathogenic:2Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Jun 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 716 of the CPS1 protein (p.Asn716Lys). This variant is present in population databases (rs369061090, gnomAD 0.005%). This missense change has been observed in individual(s) with CPS1 deficiency (PMID: 9686343, 16737834). This variant is also known as 2271T>A. ClinVar contains an entry for this variant (Variation ID: 280052). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CPS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CPS1 function (PMID: 15876373). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2020	Variant summary: CPS1 c.2148T>A (p.Asn716Lys) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) and ATP-grasp fold domain (IPR011761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250448 control chromosomes (gnomAD). c.2148T>A has been reported in the literature in individuals affected with Carbamoylphosphate Synthetase I Deficiency (e.g. Eeds_2006, Summar_1998, Summar_2004). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant interferes with the phosphorylation of bicarbonate and significantly decreases CPS activity (Yefimenko_2005). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2024

The c.2148T>A (p.N716K) alteration is located in exon 18 (coding exon 18) of the CPS1 gene. This alteration results from a T to A substitution at nucleotide position 2148, causing the asparagine (N) at amino acid position 716 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/250448) total alleles studied. The highest observed frequency was 0.004% (4/113044) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other CPS1 variants in individuals with features consistent with carbamoylphosphate synthetase I deficiency (Summar, 1998; Eeds, 2006). This amino acid position is highly conserved in available vertebrate species. In an in vitro assay performed in E.coli cells, this variant was determined to affect CPS1 activity (Yefimenko, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2016

The N716K missense variant in the CPS1 gene has been reported multiple times in patients with carbamoylphosphate synthetase I (CPS1) deficiency who were homozygous for N716K or who also harbored a second pathogenic variant in the CPS1 gene (Summar et al. 1998; Eeds et al. 2006). The N716K variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. N716K is a semi-conservative amino acid substitution, it substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant as pathogenic. -

CPS1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2024

The CPS1 c.2148T>A variant is predicted to result in the amino acid substitution p.Asn716Lys. This variant has been reported in individuals with carbamoyl phosphate synthetase I deficiency (Summar et al. 1998. PubMed ID: 9686343; Summar et al. 2004. PubMed ID: 15050969; Supplementary Table S1, Häberle et al. 2011. PubMed ID: 21120950). This variant was also introduced into E. coli and was found to impact CPS activity (reported as N301K E. coli CPS variant, Yefimenko et al. 2005. PubMed ID: 15876373). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. -

Pulmonary hypertension, neonatal, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.2

.;H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

1.0

MutPred

0.99

.;Gain of methylation at N716 (P = 0.0122);.;

MVP

0.97

MPC

0.91

ClinPred

1.0

GERP RS

3.5

Varity_R

0.98

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over