Genetic Variant CPS1:p.Arg3Lys (chr2-210556741-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001875.5(CPS1):c.8G>A(p.Arg3Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.92

Publications

2 publications found

Variant links:

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

CPS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39614886).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPS1	NM_001875.5	MANE Select	c.8G>A	p.Arg3Lys	missense	Exon 1 of 38	NP_001866.2
CPS1	NM_001369256.1		c.41G>A	p.Arg14Lys	missense	Exon 2 of 39	NP_001356185.1
CPS1	NM_001122633.3		c.8G>A	p.Arg3Lys	missense	Exon 2 of 39	NP_001116105.2	P31327-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPS1	ENST00000233072.10	TSL:1 MANE Select	c.8G>A	p.Arg3Lys	missense	Exon 1 of 38	ENSP00000233072.5	P31327-1
CPS1	ENST00000430249.7	TSL:1	c.26G>A	p.Arg9Lys	missense	Exon 2 of 39	ENSP00000402608.2	P31327-3
CPS1	ENST00000881564.1		c.8G>A	p.Arg3Lys	missense	Exon 1 of 38	ENSP00000551623.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250858

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.014

Eigen

Benign

-0.042

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.69

M_CAP

Benign

0.041

MetaRNN

Benign

0.40

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

0.0

PhyloP100

5.9

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.40

REVEL

Uncertain

0.37

Sift

Benign

0.51

Sift4G

Benign

0.33

Polyphen

0.0020

Vest4

0.54

MutPred

0.29

Gain of methylation at R3 (P = 0.0528)

MVP

0.91

MPC

0.23

ClinPred

0.71

GERP RS

5.8

PromoterAI

0.012

Neutral

(source)

Varity_R

0.30

gMVP

0.63

Mutation Taster

=77/23

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over