rs140475976
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1
The NM_001875.5(CPS1):āc.1569A>Gā(p.Arg523Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,612,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00027 ( 0 hom., cov: 32)
Exomes š: 0.00031 ( 0 hom. )
Consequence
CPS1
NM_001875.5 synonymous
NM_001875.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.26
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
Variant 2-210600574-A-G is Benign according to our data. Variant chr2-210600574-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 512285.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BP7
Synonymous conserved (PhyloP=2.26 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00027 (41/152044) while in subpopulation NFE AF= 0.00053 (36/67896). AF 95% confidence interval is 0.000393. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CPS1 | NM_001875.5 | c.1569A>G | p.Arg523Arg | synonymous_variant | 15/38 | ENST00000233072.10 | NP_001866.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000270 AC: 41AN: 151926Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000275 AC: 69AN: 250594Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135456
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GnomAD4 exome AF: 0.000308 AC: 450AN: 1460102Hom.: 0 Cov.: 31 AF XY: 0.000314 AC XY: 228AN XY: 726400
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GnomAD4 genome 0.000270 AC: 41AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74300
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital hyperammonemia, type I Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2018 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at