rs116664530

chr2-210639132-A-Gchr2-210639132-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001875.5(CPS1):c.2830-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,596,772 control chromosomes in the GnomAD database, including 630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (55 hom., cov: 32)
  • Exomes 𝑓: 0.025 (575 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.338

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-210639132-A-G is Benign according to our data. Variant chr2-210639132-A-G is described in ClinVar as [Benign]. Clinvar id is 137025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210639132-A-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.2830-18A>G		intron_variant		ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.2830-18A>G		intron_variant		1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3020 AN: 152106 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0259 AC: 6356 AN: 245054 Hom.: 146 AF XY: 0.0242 AC XY: 3204 AN XY: 132538

Gnomad AFR exome AF: 0.00361

Gnomad AMR exome AF: 0.0572

Gnomad ASJ exome AF: 0.0279

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00566

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0255 AC: 36802 AN: 1444548 Hom.: 575 Cov.: 28 AF XY: 0.0249 AC XY: 17897 AN XY: 719268

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.0535

Gnomad4 ASJ exome AF: 0.0281

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00560

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0278

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0198 AC: 3021 AN: 152224 Hom.: 55 Cov.: 32 AF XY: 0.0195 AC XY: 1454 AN XY: 74452

Gnomad4 AFR AF: 0.00452

Gnomad4 AMR AF: 0.0424

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0209

Gnomad4 NFE AF: 0.0266

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0212 Hom.: 12

Bravo AF: 0.0205

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital hyperammonemia, type I Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.6
Dann	Benign	0.26

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: rs116664530; hg19: chr2-211503856;