dbSNP rs114819130: CPS1:p.Gly150Glu (chr2-210577488-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001875.5(CPS1):c.449G>A(p.Gly150Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0104 in 1,613,504 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G150G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0061 ( 4 hom., cov: 32)

Exomes 𝑓: 0.011 ( 114 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.65

Publications

15 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: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet, G2P

CPS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014847696).

BP6

Variant 2-210577488-G-A is Benign according to our data. Variant chr2-210577488-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334013.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00613 (933/152128) while in subpopulation NFE AF = 0.0101 (685/67998). AF 95% confidence interval is 0.00945. There are 4 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPS1	NM_001875.5	MANE Select	c.449G>A	p.Gly150Glu	missense	Exon 4 of 38	NP_001866.2
CPS1	NM_001369256.1		c.482G>A	p.Gly161Glu	missense	Exon 5 of 39	NP_001356185.1
CPS1	NM_001122633.3		c.449G>A	p.Gly150Glu	missense	Exon 5 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.449G>A	p.Gly150Glu	missense	Exon 4 of 38	ENSP00000233072.5	P31327-1
CPS1	ENST00000430249.7	TSL:1	c.467G>A	p.Gly156Glu	missense	Exon 5 of 39	ENSP00000402608.2	P31327-3
CPS1	ENST00000881564.1		c.449G>A	p.Gly150Glu	missense	Exon 4 of 38	ENSP00000551623.1

Frequencies

GnomAD3 genomes

AF:

0.00614

AC:

933

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00414

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00499

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00639

AC:

1605

AN:

251346

AF XY:

0.00635

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00383

Gnomad NFE exome

AF:

0.00937

Gnomad OTH exome

AF:

0.00816

GnomAD4 exome

AF:

0.0108

AC:

15828

AN:

1461376

Hom.:

114

Cov.:

AF XY:

0.0107

AC XY:

7780

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33458

American (AMR)

AF:

0.00400

AC:

179

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

310

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00424

AC:

366

AN:

86256

European-Finnish (FIN)

AF:

0.00404

AC:

216

AN:

53420

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0126

AC:

14019

AN:

1111568

Other (OTH)

AF:

0.0112

AC:

674

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

755

1510

2266

3021

3776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

568

1136

1704

2272

2840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00613

AC:

933

AN:

152128

Hom.:

Cov.:

AF XY:

0.00565

AC XY:

420

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41528

American (AMR)

AF:

0.00413

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.00499

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00255

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0101

AC:

685

AN:

67998

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00878

Hom.:

Bravo

AF:

0.00620

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.00633

AC:

768

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0103

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital hyperammonemia, type I (4)

not provided (3)

CPS1-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.1

PhyloP100

3.7

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.028

Polyphen

0.53

Vest4

0.76

MVP

0.95

MPC

0.58

ClinPred

0.063

GERP RS

4.4

Varity_R

0.88

gMVP

0.91

Mutation Taster

=93/7

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over