2-210591913-A-G

Variant names:

• chr2-210591913-A-G
• rs1047883
• NM_001875.5:c.1030A>G

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>G​(p.Thr344Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,610,050 control chromosomes in the GnomAD database, including 260,102 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T344S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.58 (25694 hom., cov: 32)
  • Exomes 𝑓: 0.57 (234408 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• 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=0.0024514198).
• BP6: Variant 2-210591913-A-G is Benign according to our data. Variant chr2-210591913-A-G is described in ClinVar as Benign. ClinVar VariationId is 128849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.607 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>G	p.Thr344Ala	missense	Exon 10 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.1063A>G	p.Thr355Ala	missense	Exon 11 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.1030A>G	p.Thr344Ala	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>G	p.Thr344Ala	missense	Exon 10 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.1048A>G	p.Thr350Ala	missense	Exon 11 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000881564.1		c.1030A>G	p.Thr344Ala	missense	Exon 10 of 38	ENSP00000551623.1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 87841 AN: 151172 Hom.: 25660 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.640

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.567 AC: 141566 AN: 249584 AF XY: 0.573

Gnomad AFR exome AF: 0.613

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.548

Gnomad FIN exome AF: 0.634

Gnomad NFE exome AF: 0.566

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.565 AC: 824785 AN: 1458762 Hom.: 234408 Cov.: 43 AF XY: 0.568 AC XY: 412380 AN XY: 725774

African (AFR) AF: 0.621 AC: 20719 AN: 33352

American (AMR) AF: 0.480 AC: 21388 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15853 AN: 26058

East Asian (EAS) AF: 0.551 AC: 21833 AN: 39626

South Asian (SAS) AF: 0.605 AC: 52145 AN: 86150

European-Finnish (FIN) AF: 0.627 AC: 33325 AN: 53180

Middle Eastern (MID) AF: 0.649 AC: 3733 AN: 5750

European-Non Finnish (NFE) AF: 0.559 AC: 620790 AN: 1109916

Other (OTH) AF: 0.581 AC: 34999 AN: 60204

GnomAD4 genome AF: 0.581 AC: 87924 AN: 151288 Hom.: 25694 Cov.: 32 AF XY: 0.583 AC XY: 43100 AN XY: 73866

African (AFR) AF: 0.613 AC: 25288 AN: 41252

American (AMR) AF: 0.526 AC: 7976 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2124 AN: 3458

East Asian (EAS) AF: 0.567 AC: 2894 AN: 5106

South Asian (SAS) AF: 0.616 AC: 2961 AN: 4810

European-Finnish (FIN) AF: 0.637 AC: 6662 AN: 10462

Middle Eastern (MID) AF: 0.644 AC: 188 AN: 292

European-Non Finnish (NFE) AF: 0.564 AC: 38188 AN: 67714

Other (OTH) AF: 0.582 AC: 1228 AN: 2110

Alfa AF: 0.567 Hom.: 66075

Bravo AF: 0.579

TwinsUK AF: 0.565 AC: 2094

ALSPAC AF: 0.556 AC: 2143

ESP6500AA AF: 0.639 AC: 2815

ESP6500EA AF: 0.568 AC: 4881

ExAC AF: 0.568 AC: 68907

EpiCase AF: 0.574

EpiControl AF: 0.579

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Congenital hyperammonemia, type I (6)
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Pulmonary hypertension, neonatal, susceptibility to;C4082171:Congenital hyperammonemia, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.9
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.27
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Benign	0.067	T
Sift4G	Uncertain	0.036	D
Polyphen		0.0010	B
Vest4		0.12
MPC		0.22
ClinPred		0.0075	T
GERP RS		-0.92
Varity_R		0.40
gMVP		0.31
Mutation Taster		=89/11	polymorphism (auto)

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: rs1047883; hg19: chr2-211456637; COSMIC: COSV51811490; COSMIC: COSV51811490;