rs6435580

Variant names:

• chr2-210658733-C-T
• rs6435580
• NM_001875.5:c.3756+45C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001875.5(CPS1):​c.3756+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,378,736 control chromosomes in the GnomAD database, including 69,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5678 hom., cov: 32)
  • Exomes 𝑓: 0.31 (63789 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.0550
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• carbamoyl phosphate synthetase I deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-210658733-C-T is Benign according to our data. Variant chr2-210658733-C-T is described in ClinVar as Benign. ClinVar VariationId is 258482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	NM_001875.5	MANE Select	c.3756+45C>T		intron	N/A	NP_001866.2
	CPS1	NM_001369256.1		c.3789+45C>T		intron	N/A	NP_001356185.1
	CPS1	NM_001122633.3		c.3756+45C>T		intron	N/A	NP_001116105.2	P31327-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.3756+45C>T		intron	N/A	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.3774+45C>T		intron	N/A	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.2403+45C>T		intron	N/A	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37933 AN: 151986 Hom.: 5683 Cov.: 32

Gnomad AFR AF: 0.0898

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.282 AC: 69653 AN: 247160 AF XY: 0.294

Gnomad AFR exome AF: 0.0819

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.297

GnomAD4 exome AF: 0.312 AC: 383221 AN: 1226632 Hom.: 63789 Cov.: 16 AF XY: 0.316 AC XY: 196578 AN XY: 622484

African (AFR) AF: 0.0815 AC: 2356 AN: 28904

American (AMR) AF: 0.195 AC: 8644 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7458 AN: 24652

East Asian (EAS) AF: 0.0694 AC: 2673 AN: 38530

South Asian (SAS) AF: 0.334 AC: 27155 AN: 81234

European-Finnish (FIN) AF: 0.349 AC: 18199 AN: 52072

Middle Eastern (MID) AF: 0.365 AC: 1950 AN: 5342

European-Non Finnish (NFE) AF: 0.333 AC: 299007 AN: 898964

Other (OTH) AF: 0.300 AC: 15779 AN: 52678

GnomAD4 genome AF: 0.249 AC: 37931 AN: 152104 Hom.: 5678 Cov.: 32 AF XY: 0.252 AC XY: 18752 AN XY: 74336

African (AFR) AF: 0.0897 AC: 3724 AN: 41506

American (AMR) AF: 0.238 AC: 3640 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1066 AN: 3470

East Asian (EAS) AF: 0.107 AC: 554 AN: 5174

South Asian (SAS) AF: 0.324 AC: 1560 AN: 4808

European-Finnish (FIN) AF: 0.360 AC: 3807 AN: 10566

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.331 AC: 22513 AN: 67976

Other (OTH) AF: 0.264 AC: 556 AN: 2108

Alfa AF: 0.309 Hom.: 13343

Bravo AF: 0.231

Asia WGS AF: 0.195 AC: 681 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Congenital hyperammonemia, type I (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.8
DANN	Benign	0.47
PhyloP100		-0.055
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6435580; hg19: chr2-211523457; COSMIC: COSV51811850;