chr2-210556728-A-ATCT

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBA1

The ENST00000430249.7(CPS1):​c.15_16insTTC​(p.Ile5_Lys6insPhe) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,610,000 control chromosomes in the GnomAD database, including 135,416 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I5I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.46 ( 16844 hom., cov: 0)
Exomes 𝑓: 0.40 ( 118572 hom. )

Consequence

CPS1
ENST00000430249.7 inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.503
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in ENST00000430249.7. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 2-210556728-A-ATCT is Benign according to our data. Variant chr2-210556728-A-ATCT is described in ClinVar as [Benign]. Clinvar id is 203647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CPS1NM_001875.5 linkuse as main transcriptc.-4_-3insTTC 5_prime_UTR_variant 1/38 ENST00000233072.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CPS1ENST00000233072.10 linkuse as main transcriptc.-4_-3insTTC 5_prime_UTR_variant 1/381 NM_001875.5 P1P31327-1

Frequencies

GnomAD3 genomes
AF:
0.462
AC:
70024
AN:
151426
Hom.:
16788
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.581
Gnomad AMI
AF:
0.312
Gnomad AMR
AF:
0.508
Gnomad ASJ
AF:
0.448
Gnomad EAS
AF:
0.364
Gnomad SAS
AF:
0.475
Gnomad FIN
AF:
0.422
Gnomad MID
AF:
0.576
Gnomad NFE
AF:
0.394
Gnomad OTH
AF:
0.489
GnomAD3 exomes
AF:
0.438
AC:
109431
AN:
250072
Hom.:
24596
AF XY:
0.435
AC XY:
58779
AN XY:
135168
show subpopulations
Gnomad AFR exome
AF:
0.584
Gnomad AMR exome
AF:
0.521
Gnomad ASJ exome
AF:
0.446
Gnomad EAS exome
AF:
0.378
Gnomad SAS exome
AF:
0.458
Gnomad FIN exome
AF:
0.425
Gnomad NFE exome
AF:
0.397
Gnomad OTH exome
AF:
0.448
GnomAD4 exome
AF:
0.399
AC:
581701
AN:
1458456
Hom.:
118572
Cov.:
32
AF XY:
0.401
AC XY:
291067
AN XY:
725582
show subpopulations
Gnomad4 AFR exome
AF:
0.595
Gnomad4 AMR exome
AF:
0.522
Gnomad4 ASJ exome
AF:
0.441
Gnomad4 EAS exome
AF:
0.345
Gnomad4 SAS exome
AF:
0.463
Gnomad4 FIN exome
AF:
0.420
Gnomad4 NFE exome
AF:
0.381
Gnomad4 OTH exome
AF:
0.424
GnomAD4 genome
AF:
0.463
AC:
70144
AN:
151544
Hom.:
16844
Cov.:
0
AF XY:
0.466
AC XY:
34513
AN XY:
74056
show subpopulations
Gnomad4 AFR
AF:
0.582
Gnomad4 AMR
AF:
0.508
Gnomad4 ASJ
AF:
0.448
Gnomad4 EAS
AF:
0.364
Gnomad4 SAS
AF:
0.477
Gnomad4 FIN
AF:
0.422
Gnomad4 NFE
AF:
0.394
Gnomad4 OTH
AF:
0.486
Alfa
AF:
0.427
Hom.:
2968
Asia WGS
AF:
0.429
AC:
1495
AN:
3478
EpiCase
AF:
0.416
EpiControl
AF:
0.422

ClinVar

Significance: Benign
Submissions summary: Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I Benign:5
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterMay 31, 2017- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 30, 2021- -
Likely benign, no assertion criteria providedcurationSingHealth Duke-NUS Institute of Precision MedicineJun 07, 2017- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not specified Benign:4
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, flagged submissionclinical testingGeneDxMar 13, 2014The variant is found in UCD-MET panel(s). -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2Other:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 14, 2017Variant summary: The CPS1 c.-4_-3insTTC variant (also known as c.15_16insTTC based upon NM_001122633.2) involves the alteration of a 5' UTR nucleotide that 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant will not affect ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 52532/120770 control chromosomes (11669 homozygotes) at a frequency of 0.4349756, which is approximately 275 times the estimated maximal expected allele frequency of a pathogenic CPS1 variant (0.0015811). Therefore, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitterclinical testingGeneDxMay 06, 2021- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61509952; hg19: chr2-211421452; API