2-210556540-G-A

Position:

• chr2-210556540-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.4-179G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,474,476 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (92 hom.)
• Consequence: CPS1 ENST00000430249.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.86

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=-0.53).
• BP6: Variant 2-210556540-G-A is Benign according to our data. Variant chr2-210556540-G-A is described in ClinVar as [Benign]. Clinvar id is 1297986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001122633.3	c.-15-179G>A		intron_variant			NP_001116105.2
CPS1	NM_001369256.1	c.19-179G>A		intron_variant			NP_001356185.1
CPS1	NM_001369257.1	c.-15-179G>A		intron_variant			NP_001356186.1
CPS1	NR_161225.1	n.898-179G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000430249.7	c.4-179G>A		intron_variant		1		ENSP00000402608
CPS1	ENST00000673510.1	c.-15-179G>A		intron_variant				ENSP00000500537	P1
CPS1	ENST00000673630.1	c.-15-179G>A		intron_variant				ENSP00000501073	P1
CPS1	ENST00000673711.1	c.-15-179G>A		intron_variant				ENSP00000501022	P1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3134 AN: 151920 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00776

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00217 AC: 2874 AN: 1322438 Hom.: 92 Cov.: 26 AF XY: 0.00191 AC XY: 1237 AN XY: 648912

Gnomad4 AFR exome AF: 0.0793

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.00536

GnomAD4 genome AF: 0.0206 AC: 3138 AN: 152038 Hom.: 94 Cov.: 32 AF XY: 0.0202 AC XY: 1503 AN XY: 74312

Gnomad4 AFR AF: 0.0714

Gnomad4 AMR AF: 0.00768

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0258 Hom.: 14

Bravo AF: 0.0239

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.77

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: rs6732642; hg19: chr2-211421264;