rs75313076

Variant names:

• chr2-210556381-G-T
• rs75313076
• ENST00000430249.7:c.4-338G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001369256.1(CPS1):​c.19-338G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 479,756 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: CPS1 NM_001369256.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17
• Publications: 0 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: ClinGen, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-210556381-G-T is Benign according to our data. Variant chr2-210556381-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1205371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1870/152126) while in subpopulation AFR AF = 0.042 (1744/41520). AF 95% confidence interval is 0.0404. There are 33 homozygotes in GnomAd4. There are 851 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369256.1. 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_001369256.1		c.19-338G>T		intron	N/A	NP_001356185.1
	CPS1	NM_001122633.3		c.-15-338G>T		intron	N/A	NP_001116105.2	P31327-1
	CPS1	NM_001369257.1		c.-15-338G>T		intron	N/A	NP_001356186.1	P31327-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000430249.7	TSL:1	c.4-338G>T		intron	N/A	ENSP00000402608.2	P31327-3
	CPS1	ENST00000673510.1		c.-15-338G>T		intron	N/A	ENSP00000500537.1	P31327-1
	CPS1	ENST00000673630.1		c.-15-338G>T		intron	N/A	ENSP00000501073.1	P31327-1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1862 AN: 152008 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00637

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00254 AC: 325 AN: 128000 AF XY: 0.00211

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00165 AC: 542 AN: 327630 Hom.: 8 Cov.: 4 AF XY: 0.00125 AC XY: 231 AN XY: 184888

African (AFR) AF: 0.0412 AC: 392 AN: 9508

American (AMR) AF: 0.00241 AC: 67 AN: 27752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11688

East Asian (EAS) AF: 0.00 AC: 0 AN: 10534

South Asian (SAS) AF: 0.000117 AC: 7 AN: 59998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13134

Middle Eastern (MID) AF: 0.00139 AC: 4 AN: 2882

European-Non Finnish (NFE) AF: 0.000125 AC: 22 AN: 176402

Other (OTH) AF: 0.00318 AC: 50 AN: 15732

GnomAD4 genome AF: 0.0123 AC: 1870 AN: 152126 Hom.: 33 Cov.: 32 AF XY: 0.0114 AC XY: 851 AN XY: 74364

African (AFR) AF: 0.0420 AC: 1744 AN: 41520

American (AMR) AF: 0.00636 AC: 97 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67976

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00594 Hom.: 5

Bravo AF: 0.0139

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.57
PhyloP100		1.2
PromoterAI		-0.0039	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs75313076; hg19: chr2-211421105;