2-210608346-G-T

Position:

chr2-210608346-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001875.5(CPS1):c.2193-15G>T 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 0.123 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 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.141

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
CPS1	NM_001875.5 linkuse as main transcript	c.2193-15G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.2193-15G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001875.5	P1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15515

AN:

151782

Hom.:

996

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.126

AC XY:

91408

AN XY:

724766

show subpopulations

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.:

AF XY:

0.104

AC XY:

7741

AN XY:

74220

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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	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. -

not provided

Benign:1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over