rs6435580

Positions:

• chr2-210658733-C-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.3756+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,378,736 control chromosomes in the GnomAD database, including 69,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5678 hom., cov: 32)
  • Exomes 𝑓: 0.31 (63789 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.0550

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=-0.72).
• BP6: Variant 2-210658733-C-T is Benign according to our data. Variant chr2-210658733-C-T is described in ClinVar as [Benign]. Clinvar id is 258482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.3756+45C>T		intron_variant		ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.3756+45C>T		intron_variant		1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37933 AN: 151986 Hom.: 5683 Cov.: 32

Gnomad AFR AF: 0.0898

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.265

GnomAD3 exomes AF: 0.282 AC: 69653 AN: 247160 Hom.: 10943 AF XY: 0.294 AC XY: 39345 AN XY: 133662

Gnomad AFR exome AF: 0.0819

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.312 AC: 383221 AN: 1226632 Hom.: 63789 Cov.: 16 AF XY: 0.316 AC XY: 196578 AN XY: 622484

Gnomad4 AFR exome AF: 0.0815

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.303

Gnomad4 EAS exome AF: 0.0694

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.300

GnomAD4 genome AF: 0.249 AC: 37931 AN: 152104 Hom.: 5678 Cov.: 32 AF XY: 0.252 AC XY: 18752 AN XY: 74336

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.264

Alfa AF: 0.318 Hom.: 11190

Bravo AF: 0.231

Asia WGS AF: 0.195 AC: 681 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital hyperammonemia, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.8
DANN	Benign	0.47

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: rs6435580; hg19: chr2-211523457; COSMIC: COSV51811850;