rs200569046
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The ENST00000233072.10(CPS1):āc.3626T>Cā(p.Met1209Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,612,688 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.00021 ( 0 hom., cov: 28)
Exomes š: 0.00021 ( 4 hom. )
Consequence
CPS1
ENST00000233072.10 missense
ENST00000233072.10 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 7.52
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 -11 ACMG points.
PM1
In a domain ATP-grasp 2 (size 191) in uniprot entity CPSM_HUMAN there are 42 pathogenic changes around while only 15 benign (74%) in ENST00000233072.10
BP4
Computational evidence support a benign effect (MetaRNN=0.014570594).
BP6
Variant 2-210656592-T-C is Benign according to our data. Variant chr2-210656592-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210758.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000212 (32/150840) while in subpopulation EAS AF= 0.0039 (20/5124). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPS1 | NM_001875.5 | c.3626T>C | p.Met1209Thr | missense_variant | 30/38 | ENST00000233072.10 | NP_001866.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CPS1 | ENST00000233072.10 | c.3626T>C | p.Met1209Thr | missense_variant | 30/38 | 1 | NM_001875.5 | ENSP00000233072 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000212 AC: 32AN: 150732Hom.: 0 Cov.: 28
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GnomAD3 exomes AF: 0.000545 AC: 137AN: 251476Hom.: 1 AF XY: 0.000508 AC XY: 69AN XY: 135912
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GnomAD4 exome AF: 0.000207 AC: 302AN: 1461848Hom.: 4 Cov.: 35 AF XY: 0.000201 AC XY: 146AN XY: 727228
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GnomAD4 genome AF: 0.000212 AC: 32AN: 150840Hom.: 0 Cov.: 28 AF XY: 0.000272 AC XY: 20AN XY: 73580
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital hyperammonemia, type I Uncertain:1Benign:3
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 08, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Elsea Laboratory, Baylor College of Medicine | Apr 01, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 10, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;N;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
0.27
.;B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at