2-210556398-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000430249.7(CPS1):c.4-321C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 499,874 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (23 hom.)
• Consequence: CPS1 ENST00000430249.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-210556398-C-A is Benign according to our data. Variant chr2-210556398-C-A is described in ClinVar as [Benign]. Clinvar id is 1222196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001122633.3	c.-15-321C>A		intron_variant
CPS1	NM_001369256.1	c.19-321C>A		intron_variant
CPS1	NM_001369257.1	c.-15-321C>A		intron_variant
CPS1	NR_161225.1	n.898-321C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000430249.7	c.4-321C>A		intron_variant		1
CPS1	ENST00000673510.1	c.-15-321C>A		intron_variant				P1
CPS1	ENST00000673630.1	c.-15-321C>A		intron_variant				P1
CPS1	ENST00000673711.1	c.-15-321C>A		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2326 AN: 151988 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00499

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00317 AC: 405 AN: 127960 Hom.: 12 AF XY: 0.00251 AC XY: 176 AN XY: 70088

Gnomad AFR exome AF: 0.0537

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000846

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00204 AC: 709 AN: 347768 Hom.: 23 Cov.: 5 AF XY: 0.00154 AC XY: 300 AN XY: 194808

Gnomad4 AFR exome AF: 0.0550

Gnomad4 AMR exome AF: 0.00274

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000332

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000417

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.0153 AC: 2330 AN: 152106 Hom.: 55 Cov.: 32 AF XY: 0.0144 AC XY: 1074 AN XY: 74372

Gnomad4 AFR AF: 0.0534

Gnomad4 AMR AF: 0.00499

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00509 Hom.: 2

Bravo AF: 0.0173

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	16
Dann	Benign	0.63

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs73073545; hg19: chr2-211421122;