NM_001875.5:c.2448C>T

Variant names:

• chr2-210612173-C-T
• rs75395645
• NM_001875.5:c.2448C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001875.5(CPS1):​c.2448C>T​(p.Cys816Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,612,062 control chromosomes in the GnomAD database, including 529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (32 hom., cov: 32)
  • Exomes 𝑓: 0.024 (497 hom.)
• Consequence: CPS1 NM_001875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0730
• Publications: 8 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=-0.33).
• BP6: Variant 2-210612173-C-T is Benign according to our data. Variant chr2-210612173-C-T is described in ClinVar as Benign. ClinVar VariationId is 137024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.073 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0176 (2667/151806) while in subpopulation NFE AF = 0.0282 (1916/67868). AF 95% confidence interval is 0.0272. There are 32 homozygotes in GnomAd4. There are 1216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	NM_001875.5	MANE Select	c.2448C>T	p.Cys816Cys	synonymous	Exon 20 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.2481C>T	p.Cys827Cys	synonymous	Exon 21 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.2448C>T	p.Cys816Cys	synonymous	Exon 21 of 39	NP_001116105.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.2448C>T	p.Cys816Cys	synonymous	Exon 20 of 38	ENSP00000233072.5
	CPS1	ENST00000430249.7	TSL:1	c.2466C>T	p.Cys822Cys	synonymous	Exon 21 of 39	ENSP00000402608.2
	CPS1	ENST00000451903.3	TSL:1	c.1095C>T	p.Cys365Cys	synonymous	Exon 10 of 28	ENSP00000406136.2

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2667 AN: 151688 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00496

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000781

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0188 AC: 4713 AN: 250994 AF XY: 0.0191

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0244 AC: 35675 AN: 1460256 Hom.: 497 Cov.: 31 AF XY: 0.0240 AC XY: 17433 AN XY: 726490

African (AFR) AF: 0.00350 AC: 117 AN: 33388

American (AMR) AF: 0.0162 AC: 722 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 459 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00660 AC: 569 AN: 86240

European-Finnish (FIN) AF: 0.0142 AC: 757 AN: 53410

Middle Eastern (MID) AF: 0.0226 AC: 130 AN: 5756

European-Non Finnish (NFE) AF: 0.0285 AC: 31644 AN: 1110872

Other (OTH) AF: 0.0212 AC: 1277 AN: 60278

GnomAD4 genome AF: 0.0176 AC: 2667 AN: 151806 Hom.: 32 Cov.: 32 AF XY: 0.0164 AC XY: 1216 AN XY: 74152

African (AFR) AF: 0.00495 AC: 205 AN: 41444

American (AMR) AF: 0.0183 AC: 278 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3462

East Asian (EAS) AF: 0.000783 AC: 4 AN: 5108

South Asian (SAS) AF: 0.00747 AC: 36 AN: 4820

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10578

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0282 AC: 1916 AN: 67868

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.0249 Hom.: 57

Bravo AF: 0.0179

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.0284

EpiControl AF: 0.0277

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:6

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.

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

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 02, 2014

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.6
DANN	Benign	0.60
PhyloP100		-0.073
Mutation Taster		=66/34	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: rs75395645; hg19: chr2-211476897;