2-210608346-G-T

Variant names:

• chr2-210608346-G-T
• rs2287600
• NM_001875.5:c.2193-15G>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.2193-15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,608,256 control chromosomes in the GnomAD database, including 13,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (999 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12439 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.141

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=-0.9).
• BP6: Variant 2-210608346-G-T is Benign according to our data. Variant chr2-210608346-G-T is described in ClinVar as [Benign]. Clinvar id is 137023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210608346-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.2193-15G>T		intron_variant	Intron 18 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.2193-15G>T		intron_variant	Intron 18 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15515 AN: 151782 Hom.: 996 Cov.: 32

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.127 AC: 31517 AN: 249112 Hom.: 2250 AF XY: 0.127 AC XY: 17155 AN XY: 134794

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.125 AC: 182204 AN: 1456356 Hom.: 12439 Cov.: 31 AF XY: 0.126 AC XY: 91408 AN XY: 724766

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.291

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.102 AC: 15515 AN: 151900 Hom.: 999 Cov.: 32 AF XY: 0.104 AC XY: 7741 AN XY: 74220

Gnomad4 AFR AF: 0.0363

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0781 Hom.: 139

Bravo AF: 0.0979

Asia WGS AF: 0.237 AC: 822 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital hyperammonemia, type I Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2017	Variant summary: c. c.2193-15G>T in CPS1 gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this do not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.1255 (14937 / 119028 chrs tested), across multiple ethnicities, including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0015%, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign by several reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.23
DANN	Benign	0.39

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: rs2287600; hg19: chr2-211473070; COSMIC: COSV51812966; COSMIC: COSV51812966;