rs75395645

Positions:

• chr2-210612173-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001875.5(CPS1):​c.2448C>T​(p.Cys816=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,612,062 control chromosomes in the GnomAD database, including 529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (32 hom., cov: 32)
  • Exomes 𝑓: 0.024 (497 hom.)
• Consequence: CPS1 NM_001875.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0730

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 2-210612173-C-T is Benign according to our data. Variant chr2-210612173-C-T is described in ClinVar as [Benign]. Clinvar id is 137024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210612173-C-T is described in Lovd as [Benign]. Variant chr2-210612173-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.073 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2667/151806) while in subpopulation NFE AF= 0.0282 (1916/67868). AF 95% confidence interval is 0.0272. There are 32 homozygotes in gnomad4. There are 1216 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5	c.2448C>T	p.Cys816=	synonymous_variant	20/38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.2448C>T	p.Cys816=	synonymous_variant	20/38	1	NM_001875.5	ENSP00000233072	P1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2667 AN: 151688 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00496

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000781

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0188 AC: 4713 AN: 250994 Hom.: 73 AF XY: 0.0191 AC XY: 2591 AN XY: 135648

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.0163

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00719

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0244 AC: 35675 AN: 1460256 Hom.: 497 Cov.: 31 AF XY: 0.0240 AC XY: 17433 AN XY: 726490

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00660

Gnomad4 FIN exome AF: 0.0142

Gnomad4 NFE exome AF: 0.0285

Gnomad4 OTH exome AF: 0.0212

GnomAD4 genome AF: 0.0176 AC: 2667 AN: 151806 Hom.: 32 Cov.: 32 AF XY: 0.0164 AC XY: 1216 AN XY: 74152

Gnomad4 AFR AF: 0.00495

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.000783

Gnomad4 SAS AF: 0.00747

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.0282

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0241 Hom.: 25

Bravo AF: 0.0179

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.0284

EpiControl AF: 0.0277

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2014	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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.6
DANN	Benign	0.60

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: rs75395645; hg19: chr2-211476897;