rs577707531

Positions:

• chr2-210642675-GA-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001875.5(CPS1):​c.3141+15delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 1,609,884 control chromosomes in the GnomAD database, including 75 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (68 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.228

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 2-210642675-GA-G is Benign according to our data. Variant chr2-210642675-GA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334030.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr2-210642675-GA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00617 (934/151400) while in subpopulation NFE AF= 0.00869 (589/67786). AF 95% confidence interval is 0.00811. There are 7 homozygotes in gnomad4. There are 461 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5	c.3141+15delA		intron_variant		ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.3141+15delA		intron_variant		1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 934 AN: 151282 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00638

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.00897

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00869

Gnomad OTH AF: 0.00965

GnomAD3 exomes AF: 0.00709 AC: 1749 AN: 246808 Hom.: 10 AF XY: 0.00731 AC XY: 977 AN XY: 133662

Gnomad AFR exome AF: 0.000824

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0000554

Gnomad SAS exome AF: 0.000826

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00797 AC: 11624 AN: 1458484 Hom.: 68 Cov.: 30 AF XY: 0.00780 AC XY: 5661 AN XY: 725496

Gnomad4 AFR exome AF: 0.000962

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000827

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.00878

Gnomad4 OTH exome AF: 0.00822

GnomAD4 genome AF: 0.00617 AC: 934 AN: 151400 Hom.: 7 Cov.: 32 AF XY: 0.00623 AC XY: 461 AN XY: 73978

Gnomad4 AFR AF: 0.00143

Gnomad4 AMR AF: 0.00637

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00897

Gnomad4 NFE AF: 0.00869

Gnomad4 OTH AF: 0.00955

Alfa AF: 0.00865 Hom.: 3

Bravo AF: 0.00535

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2017	Variant summary: c.3141+15delA in CPS1 gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this do not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.007693 (831/108016chrs tested), predominantly in individuals of European descent (0.01209; 715/ 59126 chrs tested), including two homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0015%, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign by a reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is associated with the following publications: (PMID: 18666241) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CPS1: BS2 -

Congenital hyperammonemia, type I Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs577707531; hg19: chr2-211507399;