Variant chr2-210556728-A-ATCT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBA1

The ENST00000430249.7(CPS1):c.15_16insTTC(p.Ile5_Lys6insPhe) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,610,000 control chromosomes in the GnomAD database, including 135,416 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I5I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.46 ( 16844 hom., cov: 0)

Exomes 𝑓: 0.40 ( 118572 hom. )

Consequence

CPS1
ENST00000430249.7 inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.503

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000430249.7. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 2-210556728-A-ATCT is Benign according to our data. Variant chr2-210556728-A-ATCT is described in ClinVar as [Benign]. Clinvar id is 203647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 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.-4_-3insTTC		5_prime_UTR_variant	1/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.-4_-3insTTC		5_prime_UTR_variant	1/38	1	NM_001875.5	P1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.462

AC:

70024

AN:

151426

Hom.:

16788

Cov.:

show subpopulations

Gnomad AFR

AF:

0.581

Gnomad AMI

AF:

0.312

Gnomad AMR

AF:

0.508

Gnomad ASJ

AF:

0.448

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.475

Gnomad FIN

AF:

0.422

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.394

Gnomad OTH

AF:

0.489

GnomAD3 exomes

AF:

0.438

AC:

109431

AN:

250072

Hom.:

24596

AF XY:

0.435

AC XY:

58779

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.584

Gnomad AMR exome

AF:

0.521

Gnomad ASJ exome

AF:

0.446

Gnomad EAS exome

AF:

0.378

Gnomad SAS exome

AF:

0.458

Gnomad FIN exome

AF:

0.425

Gnomad NFE exome

AF:

0.397

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.399

AC:

581701

AN:

1458456

Hom.:

118572

Cov.:

AF XY:

0.401

AC XY:

291067

AN XY:

725582

show subpopulations

Gnomad4 AFR exome

AF:

0.595

Gnomad4 AMR exome

AF:

0.522

Gnomad4 ASJ exome

AF:

0.441

Gnomad4 EAS exome

AF:

0.345

Gnomad4 SAS exome

AF:

0.463

Gnomad4 FIN exome

AF:

0.420

Gnomad4 NFE exome

AF:

0.381

Gnomad4 OTH exome

AF:

0.424

GnomAD4 genome

AF:

0.463

AC:

70144

AN:

151544

Hom.:

16844

Cov.:

AF XY:

0.466

AC XY:

34513

AN XY:

74056

show subpopulations

Gnomad4 AFR

AF:

0.582

Gnomad4 AMR

AF:

0.508

Gnomad4 ASJ

AF:

0.448

Gnomad4 EAS

AF:

0.364

Gnomad4 SAS

AF:

0.477

Gnomad4 FIN

AF:

0.422

Gnomad4 NFE

AF:

0.394

Gnomad4 OTH

AF:

0.486

Alfa

AF:

0.427

Hom.:

2968

Asia WGS

AF:

0.429

AC:

1495

AN:

3478

EpiCase

AF:

0.416

EpiControl

AF:

0.422

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, flagged submission	clinical testing	GeneDx	Mar 13, 2014	The variant is found in UCD-MET panel(s). -

not provided

Benign:2Other: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	May 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2017	Variant summary: The CPS1 c.-4_-3insTTC variant (also known as c.15_16insTTC based upon NM_001122633.2) involves the alteration of a 5' UTR nucleotide that 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant will not affect ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 52532/120770 control chromosomes (11669 homozygotes) at a frequency of 0.4349756, which is approximately 275 times the estimated maximal expected allele frequency of a pathogenic CPS1 variant (0.0015811). Therefore, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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