chr2-210477778-G-A

Position:

• chr2-210477778-G-A

Variant summary

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

The ENST00000430249.7(CPS1):​c.3+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,610,330 control chromosomes in the GnomAD database, including 209,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15891 hom., cov: 32)
  • Exomes 𝑓: 0.51 (194061 hom.)
• Consequence: CPS1 ENST00000430249.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.39

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=-0.89).
• BP6: Variant 2-210477778-G-A is Benign according to our data. Variant chr2-210477778-G-A is described in ClinVar as [Benign]. Clinvar id is 137026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210477778-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001122633.3	c.-16+12G>A		intron_variant
CPS1	NM_001369257.1	c.-136+12G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000430249.7	c.3+12G>A		intron_variant		1
CPS1	ENST00000673510.1	c.-136+12G>A		intron_variant				P1
CPS1	ENST00000673630.1	c.-250+12G>A		intron_variant				P1
CPS1	ENST00000673711.1	c.-16+12G>A		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66809 AN: 151888 Hom.: 15891 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.593

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.443

GnomAD3 exomes AF: 0.512 AC: 126630 AN: 247172 Hom.: 33705 AF XY: 0.514 AC XY: 68998 AN XY: 134292

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.628

Gnomad SAS exome AF: 0.591

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.487

GnomAD4 exome AF: 0.512 AC: 746332 AN: 1458324 Hom.: 194061 Cov.: 35 AF XY: 0.513 AC XY: 372321 AN XY: 725490

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.597

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.586

Gnomad4 FIN exome AF: 0.485

Gnomad4 NFE exome AF: 0.512

Gnomad4 OTH exome AF: 0.488

GnomAD4 genome AF: 0.440 AC: 66819 AN: 152006 Hom.: 15891 Cov.: 32 AF XY: 0.443 AC XY: 32933 AN XY: 74286

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.503

Gnomad4 OTH AF: 0.446

Alfa AF: 0.465 Hom.: 4848

Bravo AF: 0.439

Asia WGS AF: 0.550 AC: 1910 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Congenital hyperammonemia, type I Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17552879; hg19: chr2-211342502; COSMIC: COSV52065402; COSMIC: COSV52065402;