rs61509952

Positions:

• chr2-210556728-A-ATCT

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.503

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]

ACMG classification

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
CPS1	NM_001875.5	c.-4_-3insTTC		5_prime_UTR_variant	1/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.-4_-3insTTC		5_prime_UTR_variant	1/38	1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70024 AN: 151426 Hom.: 16788 Cov.: 0

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

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

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

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:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Likely benign, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, flagged submission	clinical testing	GeneDx	Mar 13, 2014	The variant is found in UCD-MET panel(s). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2017	Variant 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 submitter	clinical testing	GeneDx	May 06, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61509952; hg19: chr2-211421452;