rs1047891

Variant names:

• chr2-210675783-C-A
• rs1047891
• NM_001875.5:c.4217C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001875.5(CPS1):​c.4217C>A​(p.Thr1406Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,606,716 control chromosomes in the GnomAD database, including 79,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8199 hom., cov: 33)
  • Exomes 𝑓: 0.31 (70851 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 1.82
• Publications: 253 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003946036).
• BP6: Variant 2-210675783-C-A is Benign according to our data. Variant chr2-210675783-C-A is described in ClinVar as Benign. ClinVar VariationId is 128852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.4217C>A	p.Thr1406Asn	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.4217C>A	p.Thr1406Asn	missense_variant	Exon 36 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49578 AN: 151970 Hom.: 8188 Cov.: 33

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.304 AC: 76336 AN: 251072 AF XY: 0.305

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.303

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.309 AC: 449492 AN: 1454628 Hom.: 70851 Cov.: 29 AF XY: 0.309 AC XY: 223650 AN XY: 724140

African (AFR) AF: 0.364 AC: 12124 AN: 33318

American (AMR) AF: 0.304 AC: 13584 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 8507 AN: 26084

East Asian (EAS) AF: 0.163 AC: 6449 AN: 39674

South Asian (SAS) AF: 0.295 AC: 25419 AN: 86128

European-Finnish (FIN) AF: 0.329 AC: 17544 AN: 53392

Middle Eastern (MID) AF: 0.327 AC: 1883 AN: 5750

European-Non Finnish (NFE) AF: 0.312 AC: 345334 AN: 1105438

Other (OTH) AF: 0.310 AC: 18648 AN: 60164

GnomAD4 genome AF: 0.326 AC: 49617 AN: 152088 Hom.: 8199 Cov.: 33 AF XY: 0.327 AC XY: 24287 AN XY: 74346

African (AFR) AF: 0.366 AC: 15166 AN: 41468

American (AMR) AF: 0.312 AC: 4763 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1128 AN: 3466

East Asian (EAS) AF: 0.157 AC: 810 AN: 5170

South Asian (SAS) AF: 0.294 AC: 1414 AN: 4816

European-Finnish (FIN) AF: 0.354 AC: 3747 AN: 10584

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21512 AN: 67990

Other (OTH) AF: 0.321 AC: 678 AN: 2114

Alfa AF: 0.316 Hom.: 19898

Bravo AF: 0.326

TwinsUK AF: 0.313 AC: 1161

ALSPAC AF: 0.314 AC: 1212

ESP6500AA AF: 0.364 AC: 1605

ESP6500EA AF: 0.311 AC: 2676

ExAC AF: 0.303 AC: 36847

Asia WGS AF: 0.245 AC: 856 AN: 3478

EpiCase AF: 0.314

EpiControl AF: 0.304

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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. -

Jun 18, 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. -

-

PreventionGenetics, part of Exact Sciences

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital hyperammonemia, type I Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 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

- -

Mar 06, 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

- -

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	0.085
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;L;.
PhyloP100		1.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0090	.;B;.
Vest4		0.054
MPC		0.26
ClinPred		0.0052	T
GERP RS		5.2
Varity_R		0.43
gMVP		0.67
Mutation Taster		=81/19	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: rs1047891; hg19: chr2-211540507; COSMIC: COSV51808344;