2-210591915-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001875.5(CPS1):​c.1032C>T​(p.Thr344Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,610,134 control chromosomes in the GnomAD database, including 262,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 26997 hom., cov: 32)
Exomes 𝑓: 0.57 ( 235876 hom. )

Consequence

CPS1
NM_001875.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.678

Publications

26 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
Variant 2-210591915-C-T is Benign according to our data. Variant chr2-210591915-C-T is described in ClinVar as [Benign]. Clinvar id is 128850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.678 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPS1NM_001875.5 linkc.1032C>T p.Thr344Thr synonymous_variant Exon 10 of 38 ENST00000233072.10 NP_001866.2 P31327-1A0A024R454Q6PEK7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPS1ENST00000233072.10 linkc.1032C>T p.Thr344Thr synonymous_variant Exon 10 of 38 1 NM_001875.5 ENSP00000233072.5 P31327-1

Frequencies

GnomAD3 genomes
AF:
0.595
AC:
89923
AN:
151206
Hom.:
26962
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.660
Gnomad AMI
AF:
0.457
Gnomad AMR
AF:
0.532
Gnomad ASJ
AF:
0.614
Gnomad EAS
AF:
0.567
Gnomad SAS
AF:
0.616
Gnomad FIN
AF:
0.636
Gnomad MID
AF:
0.643
Gnomad NFE
AF:
0.564
Gnomad OTH
AF:
0.589
GnomAD2 exomes
AF:
0.571
AC:
142506
AN:
249724
AF XY:
0.576
show subpopulations
Gnomad AFR exome
AF:
0.664
Gnomad AMR exome
AF:
0.473
Gnomad ASJ exome
AF:
0.618
Gnomad EAS exome
AF:
0.547
Gnomad FIN exome
AF:
0.633
Gnomad NFE exome
AF:
0.566
Gnomad OTH exome
AF:
0.580
GnomAD4 exome
AF:
0.567
AC:
827090
AN:
1458812
Hom.:
235876
Cov.:
43
AF XY:
0.570
AC XY:
413364
AN XY:
725806
show subpopulations
African (AFR)
AF:
0.676
AC:
22539
AN:
33354
American (AMR)
AF:
0.483
AC:
21502
AN:
44534
Ashkenazi Jewish (ASJ)
AF:
0.608
AC:
15858
AN:
26066
East Asian (EAS)
AF:
0.551
AC:
21833
AN:
39622
South Asian (SAS)
AF:
0.605
AC:
52164
AN:
86160
European-Finnish (FIN)
AF:
0.627
AC:
33327
AN:
53184
Middle Eastern (MID)
AF:
0.654
AC:
3759
AN:
5748
European-Non Finnish (NFE)
AF:
0.559
AC:
620897
AN:
1109934
Other (OTH)
AF:
0.585
AC:
35211
AN:
60210
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.439
Heterozygous variant carriers
0
19907
39814
59722
79629
99536
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
17376
34752
52128
69504
86880
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.595
AC:
90009
AN:
151322
Hom.:
26997
Cov.:
32
AF XY:
0.597
AC XY:
44121
AN XY:
73902
show subpopulations
African (AFR)
AF:
0.661
AC:
27239
AN:
41224
American (AMR)
AF:
0.531
AC:
8061
AN:
15188
Ashkenazi Jewish (ASJ)
AF:
0.614
AC:
2124
AN:
3460
East Asian (EAS)
AF:
0.567
AC:
2896
AN:
5110
South Asian (SAS)
AF:
0.616
AC:
2964
AN:
4812
European-Finnish (FIN)
AF:
0.636
AC:
6661
AN:
10478
Middle Eastern (MID)
AF:
0.647
AC:
189
AN:
292
European-Non Finnish (NFE)
AF:
0.564
AC:
38214
AN:
67740
Other (OTH)
AF:
0.591
AC:
1246
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1847
3694
5542
7389
9236
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
756
1512
2268
3024
3780
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.575
Hom.:
16341
Bravo
AF:
0.585
Asia WGS
AF:
0.629
AC:
2184
AN:
3476
EpiCase
AF:
0.574
EpiControl
AF:
0.579

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 10, 2015
Eurofins Ntd Llc (ga)
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

- -

-
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. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jul 25, 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. -

Congenital hyperammonemia, type I Benign:6
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

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 10, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.38
CADD
Benign
8.7
DANN
Benign
0.56
PhyloP100
0.68
Mutation Taster
=62/38
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

Publications

Other links and lift over

dbSNP: rs2229589; hg19: chr2-211456639; COSMIC: COSV51802456; COSMIC: COSV51802456; API