NM_001875.5:c.2227delC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001875.5(CPS1):c.2227delC(p.Leu743fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CPS1
NM_001875.5 frameshift
NM_001875.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.77
Publications
1 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 diseaseInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-210608392-GC-G is Pathogenic according to our data. Variant chr2-210608392-GC-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 557529.Status of the report is no_assertion_criteria_provided, 0 stars.
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.2227delC | p.Leu743fs | frameshift | Exon 19 of 38 | NP_001866.2 | ||
| CPS1 | NM_001369256.1 | c.2260delC | p.Leu754fs | frameshift | Exon 20 of 39 | NP_001356185.1 | |||
| CPS1 | NM_001122633.3 | c.2227delC | p.Leu743fs | frameshift | Exon 20 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.2227delC | p.Leu743fs | frameshift | Exon 19 of 38 | ENSP00000233072.5 | ||
| CPS1 | ENST00000430249.7 | TSL:1 | c.2245delC | p.Leu749fs | frameshift | Exon 20 of 39 | ENSP00000402608.2 | ||
| CPS1 | ENST00000451903.3 | TSL:1 | c.874delC | p.Leu292fs | frameshift | Exon 9 of 28 | ENSP00000406136.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250752 AF XY: 0.00000738 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
250752
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460218Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726496 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1460218
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
726496
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33364
American (AMR)
AF:
AC:
0
AN:
44616
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26038
East Asian (EAS)
AF:
AC:
0
AN:
39674
South Asian (SAS)
AF:
AC:
0
AN:
86220
European-Finnish (FIN)
AF:
AC:
0
AN:
53338
Middle Eastern (MID)
AF:
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1110952
Other (OTH)
AF:
AC:
0
AN:
60266
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Congenital hyperammonemia, type I Pathogenic:2
Mar 06, 2025
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
Mar 28, 2018
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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