NM_001875.5:c.2679C>G

Variant names:

• chr2-210616533-C-G
• rs2287599
• NM_001875.5:c.2679C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001875.5(CPS1):​c.2679C>G​(p.Gly893Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,585,376 control chromosomes in the GnomAD database, including 264,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33015 hom., cov: 31)
  • Exomes 𝑓: 0.56 (231606 hom.)
• Consequence: CPS1 NM_001875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.233
• Publications: 30 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-210616533-C-G is Benign according to our data. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210616533-C-G is described in CliVar as Benign. Clinvar id is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.233 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.2679C>G	p.Gly893Gly	synonymous_variant	Exon 21 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.2679C>G	p.Gly893Gly	synonymous_variant	Exon 21 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97609 AN: 151646 Hom.: 32953 Cov.: 31

Gnomad AFR AF: 0.863

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.630

GnomAD2 exomes AF: 0.578 AC: 144700 AN: 250550 AF XY: 0.580

Gnomad AFR exome AF: 0.867

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.498

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.564 AC: 808754 AN: 1433612 Hom.: 231606 Cov.: 27 AF XY: 0.567 AC XY: 405554 AN XY: 715026

African (AFR) AF: 0.878 AC: 28745 AN: 32748

American (AMR) AF: 0.487 AC: 21696 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 15918 AN: 25840

East Asian (EAS) AF: 0.513 AC: 20273 AN: 39536

South Asian (SAS) AF: 0.632 AC: 54122 AN: 85626

European-Finnish (FIN) AF: 0.568 AC: 30268 AN: 53312

Middle Eastern (MID) AF: 0.671 AC: 3824 AN: 5700

European-Non Finnish (NFE) AF: 0.551 AC: 598717 AN: 1086908

Other (OTH) AF: 0.593 AC: 35191 AN: 59392

GnomAD4 genome AF: 0.644 AC: 97724 AN: 151764 Hom.: 33015 Cov.: 31 AF XY: 0.643 AC XY: 47734 AN XY: 74180

African (AFR) AF: 0.864 AC: 35818 AN: 41462

American (AMR) AF: 0.544 AC: 8289 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2171 AN: 3466

East Asian (EAS) AF: 0.515 AC: 2641 AN: 5126

South Asian (SAS) AF: 0.638 AC: 3063 AN: 4804

European-Finnish (FIN) AF: 0.577 AC: 6094 AN: 10554

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37662 AN: 67808

Other (OTH) AF: 0.633 AC: 1339 AN: 2116

Alfa AF: 0.585 Hom.: 8674

Bravo AF: 0.645

Asia WGS AF: 0.624 AC: 2170 AN: 3478

EpiCase AF: 0.572

EpiControl AF: 0.577

ClinVar

Significance: Benign

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:6

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 25, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

May 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CPS1 c.2679C>G (p.Gly893Gly) variant involves the alteration of a non-conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may remove ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 71012/121158 control chromosomes (21467 homozygotes) at a frequency of 0.5861107, which is approximately 371 times the estimated maximal expected allele frequency of a pathogenic CPS1 variant (0.0015811) and indicates that the variant is the major allele (the allele most commonly seen in the general population). Therefore, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.2
DANN	Benign	0.69
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2287599; hg19: chr2-211481257; COSMIC: COSV51802474; COSMIC: COSV51802474;