2-210556705-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000430249.7(CPS1):c.4-14T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,601,440 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (127 hom.)
• Consequence: CPS1 ENST00000430249.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.494

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=-0.75).
• BP6: Variant 2-210556705-T-G is Benign according to our data. Variant chr2-210556705-T-G is described in ClinVar as [Benign]. Clinvar id is 334007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210556705-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00891 (1272/142758) while in subpopulation SAS AF= 0.0236 (103/4364). AF 95% confidence interval is 0.0199. There are 9 homozygotes in gnomad4. There are 662 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5	c.-29T>G		5_prime_UTR_variant	1/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10	c.-29T>G		5_prime_UTR_variant	1/38	1	NM_001875.5	P1

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1272 AN: 142668 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0235

Gnomad FIN AF: 0.00973

Gnomad MID AF: 0.0205

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0135

GnomAD3 exomes AF: 0.0116 AC: 2858 AN: 246558 Hom.: 29 AF XY: 0.0128 AC XY: 1707 AN XY: 133622

Gnomad AFR exome AF: 0.000832

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.000330

Gnomad SAS exome AF: 0.0258

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0104 AC: 15157 AN: 1458682 Hom.: 127 Cov.: 31 AF XY: 0.0109 AC XY: 7908 AN XY: 725710

Gnomad4 AFR exome AF: 0.000902

Gnomad4 AMR exome AF: 0.00632

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0246

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.00959

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.00891 AC: 1272 AN: 142758 Hom.: 9 Cov.: 32 AF XY: 0.00952 AC XY: 662 AN XY: 69508

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.00973

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.0134

Alfa AF: 0.0111 Hom.: 5

Bravo AF: 0.00691

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2016

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. -

CPS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital hyperammonemia, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.75
Cadd	Benign	5.8
Dann	Benign	0.59

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: rs147937942; hg19: chr2-211421429;