2-210678331-T-C

Position:

• chr2-210678331-T-C

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.*346T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 355,210 control chromosomes in the GnomAD database, including 15,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6148 hom., cov: 32)
  • Exomes 𝑓: 0.30 (9181 hom.)
• Consequence: CPS1 NM_001875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.83

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]

CPS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-210678331-T-C is Benign according to our data. Variant chr2-210678331-T-C is described in ClinVar as [Benign]. Clinvar id is 334042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5	c.*346T>C		3_prime_UTR_variant	38/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.*346T>C		3_prime_UTR_variant	38/38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42453 AN: 151988 Hom.: 6142 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.297 AC: 60254 AN: 203104 Hom.: 9181 Cov.: 0 AF XY: 0.298 AC XY: 32906 AN XY: 110454

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.323

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.279 AC: 42473 AN: 152106 Hom.: 6148 Cov.: 32 AF XY: 0.280 AC XY: 20855 AN XY: 74360

Gnomad4 AFR AF: 0.206

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.314

Gnomad4 OTH AF: 0.283

Alfa AF: 0.299 Hom.: 2521

Bravo AF: 0.273

Asia WGS AF: 0.239 AC: 834 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Congenital hyperammonemia, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.63

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: rs715; hg19: chr2-211543055;