2-210648491-G-A

Variant names:

• chr2-210648491-G-A
• rs76340296
• NM_001875.5:c.3355G>A

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.3355G>A​(p.Ala1119Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00248 in 1,613,204 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1119V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (51 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (42 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.08
• Publications: 5 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 (MetaRNN=0.0064868033).
• BP6: Variant 2-210648491-G-A is Benign according to our data. Variant chr2-210648491-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235274.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 = 0.0134 (2042/152282) while in subpopulation AFR AF = 0.0464 (1926/41552). AF 95% confidence interval is 0.0446. There are 51 homozygotes in GnomAd4. There are 959 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 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.3355G>A	p.Ala1119Thr	missense	Exon 27 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.3388G>A	p.Ala1130Thr	missense	Exon 28 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.3355G>A	p.Ala1119Thr	missense	Exon 28 of 39	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.3355G>A	p.Ala1119Thr	missense	Exon 27 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.3373G>A	p.Ala1125Thr	missense	Exon 28 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.2002G>A	p.Ala668Thr	missense	Exon 17 of 28	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2040 AN: 152164 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.0464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00337 AC: 847 AN: 251162 AF XY: 0.00250

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00135 AC: 1965 AN: 1460922 Hom.: 42 Cov.: 30 AF XY: 0.00121 AC XY: 878 AN XY: 726848

African (AFR) AF: 0.0488 AC: 1629 AN: 33412

American (AMR) AF: 0.00244 AC: 109 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111426

Other (OTH) AF: 0.00283 AC: 171 AN: 60370

GnomAD4 genome AF: 0.0134 AC: 2042 AN: 152282 Hom.: 51 Cov.: 33 AF XY: 0.0129 AC XY: 959 AN XY: 74442

African (AFR) AF: 0.0464 AC: 1926 AN: 41552

American (AMR) AF: 0.00575 AC: 88 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68008

Other (OTH) AF: 0.0114 AC: 24 AN: 2110

Alfa AF: 0.00492 Hom.: 29

Bravo AF: 0.0155

ESP6500AA AF: 0.0472 AC: 208

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00420 AC: 510

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0065	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.64
Sift	Benign	0.034	D
Sift4G	Benign	0.10	T
Polyphen		0.37	B
Vest4		0.44
MVP		0.96
MPC		0.31
ClinPred		0.078	T
GERP RS		6.2
Varity_R		0.63
gMVP		0.88
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76340296; hg19: chr2-211513215;