2-210591913-A-T

Variant names:

• chr2-210591913-A-T
• rs1047883
• NM_001875.5:c.1030A>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.1030A>T​(p.Thr344Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,611,196 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T344A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (59 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.266
• Publications: 47 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=0.0035771728).
• BP6: Variant 2-210591913-A-T is Benign according to our data. Variant chr2-210591913-A-T is described in ClinVar as Benign. ClinVar VariationId is 281331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 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.1030A>T	p.Thr344Ser	missense	Exon 10 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.1063A>T	p.Thr355Ser	missense	Exon 11 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.1030A>T	p.Thr344Ser	missense	Exon 11 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.1030A>T	p.Thr344Ser	missense	Exon 10 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.1048A>T	p.Thr350Ser	missense	Exon 11 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000881564.1		c.1030A>T	p.Thr344Ser	missense	Exon 10 of 38	ENSP00000551623.1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2108 AN: 151268 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00534

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000310

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00372 AC: 929 AN: 249584 AF XY: 0.00293

Gnomad AFR exome AF: 0.0503

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00156 AC: 2281 AN: 1459812 Hom.: 59 Cov.: 43 AF XY: 0.00133 AC XY: 966 AN XY: 726220

African (AFR) AF: 0.0544 AC: 1815 AN: 33366

American (AMR) AF: 0.00251 AC: 112 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00487 AC: 28 AN: 5754

European-Non Finnish (NFE) AF: 0.0000909 AC: 101 AN: 1110746

Other (OTH) AF: 0.00349 AC: 210 AN: 60232

GnomAD4 genome AF: 0.0139 AC: 2111 AN: 151384 Hom.: 46 Cov.: 32 AF XY: 0.0139 AC XY: 1026 AN XY: 73926

African (AFR) AF: 0.0482 AC: 1989 AN: 41290

American (AMR) AF: 0.00533 AC: 81 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10470

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000310 AC: 21 AN: 67734

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

Alfa AF: 0.0000417 Hom.: 66075

ExAC AF: 0.00438 AC: 531

EpiCase AF: 0.000382

EpiControl AF: 0.000535

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.052
DANN	Benign	0.74
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.080	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.33	N
PhyloP100		0.27
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.30
Sift	Benign	0.59	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.23		Loss of sheet (P = 0.0817)
MVP		0.65
MPC		0.20
ClinPred		0.0021	T
GERP RS		-0.92
Varity_R		0.17
gMVP		0.22
Mutation Taster		=90/10	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: rs1047883; hg19: chr2-211456637;