chr2-210556705-T-G

Variant names:

• chr2-210556705-T-G
• rs147937942
• NM_001875.5:c.-29T>G

Variant summary

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

The NM_001875.5(CPS1):​c.-29T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,601,440 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (127 hom.)
• Consequence: CPS1 NM_001875.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.494
• Publications: 3 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=-0.75).
• BP6: Variant 2-210556705-T-G is Benign according to our data. Variant chr2-210556705-T-G is described in ClinVar as Benign. ClinVar VariationId is 334007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00891 (1272/142758) while in subpopulation SAS AF = 0.0236 (103/4364). AF 95% confidence interval is 0.0199. There are 9 homozygotes in GnomAd4. There are 662 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

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.-29T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 38	NP_001866.2
	CPS1	NM_001875.5	MANE Select	c.-29T>G		5_prime_UTR	Exon 1 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.19-14T>G		intron	N/A	NP_001356185.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.-29T>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.-29T>G		5_prime_UTR	Exon 1 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.4-14T>G		intron	N/A	ENSP00000402608.2	P31327-3

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1272 AN: 142668 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0235

Gnomad FIN AF: 0.00973

Gnomad MID AF: 0.0205

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0135

GnomAD2 exomes AF: 0.0116 AC: 2858 AN: 246558 AF XY: 0.0128

Gnomad AFR exome AF: 0.000832

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.000330

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0104 AC: 15157 AN: 1458682 Hom.: 127 Cov.: 31 AF XY: 0.0109 AC XY: 7908 AN XY: 725710

African (AFR) AF: 0.000902 AC: 30 AN: 33254

American (AMR) AF: 0.00632 AC: 280 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 714 AN: 25980

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39652

South Asian (SAS) AF: 0.0246 AC: 2110 AN: 85886

European-Finnish (FIN) AF: 0.0122 AC: 650 AN: 53362

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5746

European-Non Finnish (NFE) AF: 0.00959 AC: 10643 AN: 1110300

Other (OTH) AF: 0.0107 AC: 645 AN: 60216

GnomAD4 genome AF: 0.00891 AC: 1272 AN: 142758 Hom.: 9 Cov.: 32 AF XY: 0.00952 AC XY: 662 AN XY: 69508

African (AFR) AF: 0.00181 AC: 67 AN: 37090

American (AMR) AF: 0.0140 AC: 195 AN: 13880

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 104 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4992

South Asian (SAS) AF: 0.0236 AC: 103 AN: 4364

European-Finnish (FIN) AF: 0.00973 AC: 97 AN: 9968

Middle Eastern (MID) AF: 0.0221 AC: 6 AN: 272

European-Non Finnish (NFE) AF: 0.0102 AC: 674 AN: 65976

Other (OTH) AF: 0.0134 AC: 26 AN: 1942

Alfa AF: 0.00914 Hom.: 5

Bravo AF: 0.00691

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital hyperammonemia, type I (1)
-	-	1	CPS1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.8
DANN	Benign	0.59
PhyloP100		0.49
PromoterAI		-0.014	Neutral
Mutation Taster		=300/0	polymorphism

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: rs147937942; hg19: chr2-211421429;