rs61509952

Variant names:

• chr2-210556728-A-ATCT
• rs61509952
• ENST00000430249.7:c.15_16insTTC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_001369256.1(CPS1):​c.30_31insTTC​(p.Ile10_Lys11insPhe) variant causes a conservative 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16844 hom., cov: 0)
  • Exomes 𝑓: 0.40 (118572 hom.)
• Consequence: CPS1 NM_001369256.1 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.503

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

Our verdict: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001369256.1. 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 rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.-4_-3insTTC		5_prime_UTR_variant	Exon 1 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072	c.-4_-3insTTC		5_prime_UTR_variant	Exon 1 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70024 AN: 151426 Hom.: 16788 Cov.: 0

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

GnomAD2 exomes AF: 0.438 AC: 109431 AN: 250072 AF XY: 0.435

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 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.: 32 AF XY: 0.401 AC XY: 291067 AN XY: 725582

Gnomad4 AFR exome AF: 0.595 AC: 19858 AN: 33350

Gnomad4 AMR exome AF: 0.522 AC: 23250 AN: 44522

Gnomad4 ASJ exome AF: 0.441 AC: 11485 AN: 26046

Gnomad4 EAS exome AF: 0.345 AC: 13667 AN: 39652

Gnomad4 SAS exome AF: 0.463 AC: 39900 AN: 86094

Gnomad4 FIN exome AF: 0.420 AC: 22434 AN: 53384

Gnomad4 NFE exome AF: 0.381 AC: 422259 AN: 1109386

Gnomad4 Remaining exome AF: 0.424 AC: 25567 AN: 60264

GnomAD4 genome AF: 0.463 AC: 70144 AN: 151544 Hom.: 16844 Cov.: 0 AF XY: 0.466 AC XY: 34513 AN XY: 74056

Gnomad4 AFR AF: 0.582 AC: 0.581958 AN: 0.581958

Gnomad4 AMR AF: 0.508 AC: 0.508496 AN: 0.508496

Gnomad4 ASJ AF: 0.448 AC: 0.448067 AN: 0.448067

Gnomad4 EAS AF: 0.364 AC: 0.364453 AN: 0.364453

Gnomad4 SAS AF: 0.477 AC: 0.476546 AN: 0.476546

Gnomad4 FIN AF: 0.422 AC: 0.422374 AN: 0.422374

Gnomad4 NFE AF: 0.394 AC: 0.394377 AN: 0.394377

Gnomad4 OTH AF: 0.486 AC: 0.48619 AN: 0.48619

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:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:5

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2014

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

The variant is found in UCD-MET panel(s). -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

May 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61509952; hg19: chr2-211421452; COSMIC: COSV51801191; COSMIC: COSV51801191;