chr2-210608433-C-A

Position:

• chr2-210608433-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000233072.10(CPS1):​c.2265C>A​(p.Ser755=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,612,368 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S755S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 32)
  • Exomes 𝑓: 0.013 (177 hom.)
• Consequence: CPS1 ENST00000233072.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.59

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-210608433-C-A is Benign according to our data. Variant chr2-210608433-C-A is described in ClinVar as [Benign]. Clinvar id is 258478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210608433-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1818/151904) while in subpopulation NFE AF= 0.0172 (1168/67886). AF 95% confidence interval is 0.0164. There are 19 homozygotes in gnomad4. There are 947 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5	c.2265C>A	p.Ser755=	synonymous_variant	19/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.2265C>A	p.Ser755=	synonymous_variant	19/38	1	NM_001875.5	ENSP00000233072	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1820 AN: 151786 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00493

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.0125 AC: 3137 AN: 250836 Hom.: 48 AF XY: 0.0124 AC XY: 1684 AN XY: 135582

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0395

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0131 AC: 19144 AN: 1460464 Hom.: 177 Cov.: 32 AF XY: 0.0130 AC XY: 9427 AN XY: 726600

Gnomad4 AFR exome AF: 0.00186

Gnomad4 AMR exome AF: 0.00426

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0120 AC: 1818 AN: 151904 Hom.: 19 Cov.: 32 AF XY: 0.0128 AC XY: 947 AN XY: 74238

Gnomad4 AFR AF: 0.00227

Gnomad4 AMR AF: 0.00492

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0390

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.0110 Hom.: 4

Bravo AF: 0.00868

EpiCase AF: 0.0118

EpiControl AF: 0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:3

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2016	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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CPS1: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.056
DANN	Benign	0.63

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: rs41272667; hg19: chr2-211473157;