NM_001875.5:c.1032C>T

Variant names:

• chr2-210591915-C-T
• rs2229589
• NM_001875.5:c.1032C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001875.5(CPS1):​c.1032C>T​(p.Thr344Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,610,134 control chromosomes in the GnomAD database, including 262,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26997 hom., cov: 32)
  • Exomes 𝑓: 0.57 (235876 hom.)
• Consequence: CPS1 NM_001875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.678
• Publications: 26 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-210591915-C-T is Benign according to our data. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210591915-C-T is described in CliVar as Benign. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.678 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.1032C>T	p.Thr344Thr	synonymous_variant	Exon 10 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.1032C>T	p.Thr344Thr	synonymous_variant	Exon 10 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.595 AC: 89923 AN: 151206 Hom.: 26962 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.589

GnomAD2 exomes AF: 0.571 AC: 142506 AN: 249724 AF XY: 0.576

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.547

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.566

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.567 AC: 827090 AN: 1458812 Hom.: 235876 Cov.: 43 AF XY: 0.570 AC XY: 413364 AN XY: 725806

African (AFR) AF: 0.676 AC: 22539 AN: 33354

American (AMR) AF: 0.483 AC: 21502 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15858 AN: 26066

East Asian (EAS) AF: 0.551 AC: 21833 AN: 39622

South Asian (SAS) AF: 0.605 AC: 52164 AN: 86160

European-Finnish (FIN) AF: 0.627 AC: 33327 AN: 53184

Middle Eastern (MID) AF: 0.654 AC: 3759 AN: 5748

European-Non Finnish (NFE) AF: 0.559 AC: 620897 AN: 1109934

Other (OTH) AF: 0.585 AC: 35211 AN: 60210

GnomAD4 genome AF: 0.595 AC: 90009 AN: 151322 Hom.: 26997 Cov.: 32 AF XY: 0.597 AC XY: 44121 AN XY: 73902

African (AFR) AF: 0.661 AC: 27239 AN: 41224

American (AMR) AF: 0.531 AC: 8061 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2124 AN: 3460

East Asian (EAS) AF: 0.567 AC: 2896 AN: 5110

South Asian (SAS) AF: 0.616 AC: 2964 AN: 4812

European-Finnish (FIN) AF: 0.636 AC: 6661 AN: 10478

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.564 AC: 38214 AN: 67740

Other (OTH) AF: 0.591 AC: 1246 AN: 2110

Alfa AF: 0.575 Hom.: 16341

Bravo AF: 0.585

Asia WGS AF: 0.629 AC: 2184 AN: 3476

EpiCase AF: 0.574

EpiControl AF: 0.579

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Congenital hyperammonemia, type I Benign:6

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

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

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

- -

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

- -

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.7
DANN	Benign	0.56
PhyloP100		0.68
Mutation Taster		=62/38	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: rs2229589; hg19: chr2-211456639; COSMIC: COSV51802456; COSMIC: COSV51802456;