dbSNP rs2287599: CPS1:p.Gly893Gly (chr2-210616533-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001875.5(CPS1):c.2679C>G(p.Gly893Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,585,376 control chromosomes in the GnomAD database, including 264,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 33015 hom., cov: 31)

Exomes 𝑓: 0.56 ( 231606 hom. )

Consequence

CPS1
NM_001875.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: -0.233

Publications

30 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), G2P, ClinGen, Myriad Women's Health, Orphanet

CPS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001875.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 2-210616533-C-G is Benign according to our data. Variant chr2-210616533-C-G is described in ClinVar as Benign. ClinVar VariationId is 128851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.233 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPS1	NM_001875.5	MANE Select	c.2679C>G	p.Gly893Gly	synonymous	Exon 21 of 38	NP_001866.2
CPS1	NM_001369256.1		c.2712C>G	p.Gly904Gly	synonymous	Exon 22 of 39	NP_001356185.1
CPS1	NM_001122633.3		c.2679C>G	p.Gly893Gly	synonymous	Exon 22 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.2679C>G	p.Gly893Gly	synonymous	Exon 21 of 38	ENSP00000233072.5	P31327-1
CPS1	ENST00000430249.7	TSL:1	c.2697C>G	p.Gly899Gly	synonymous	Exon 22 of 39	ENSP00000402608.2	P31327-3
CPS1	ENST00000451903.3	TSL:1	c.1326C>G	p.Gly442Gly	synonymous	Exon 11 of 28	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes

AF:

0.644

AC:

97609

AN:

151646

Hom.:

32953

Cov.:

show subpopulations

Gnomad AFR

AF:

0.863

Gnomad AMI

AF:

0.501

Gnomad AMR

AF:

0.545

Gnomad ASJ

AF:

0.626

Gnomad EAS

AF:

0.516

Gnomad SAS

AF:

0.637

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.555

Gnomad OTH

AF:

0.630

GnomAD2 exomes

AF:

0.578

AC:

144700

AN:

250550

AF XY:

0.580

show subpopulations

Gnomad AFR exome

AF:

0.867

Gnomad AMR exome

AF:

0.477

Gnomad ASJ exome

AF:

0.624

Gnomad EAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.573

Gnomad NFE exome

AF:

0.562

Gnomad OTH exome

AF:

0.579

GnomAD4 exome

AF:

0.564

AC:

808754

AN:

1433612

Hom.:

231606

Cov.:

AF XY:

0.567

AC XY:

405554

AN XY:

715026

show subpopulations

African (AFR)

AF:

0.878

AC:

28745

AN:

32748

American (AMR)

AF:

0.487

AC:

21696

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.616

AC:

15918

AN:

25840

East Asian (EAS)

AF:

0.513

AC:

20273

AN:

39536

South Asian (SAS)

AF:

0.632

AC:

54122

AN:

85626

European-Finnish (FIN)

AF:

0.568

AC:

30268

AN:

53312

Middle Eastern (MID)

AF:

0.671

AC:

3824

AN:

5700

European-Non Finnish (NFE)

AF:

0.551

AC:

598717

AN:

1086908

Other (OTH)

AF:

0.593

AC:

35191

AN:

59392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

16159

32317

48476

64634

80793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16742

33484

50226

66968

83710

<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:

0.644

AC:

97724

AN:

151764

Hom.:

33015

Cov.:

AF XY:

0.643

AC XY:

47734

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.864

AC:

35818

AN:

41462

American (AMR)

AF:

0.544

AC:

8289

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.626

AC:

2171

AN:

3466

East Asian (EAS)

AF:

0.515

AC:

2641

AN:

5126

South Asian (SAS)

AF:

0.638

AC:

3063

AN:

4804

European-Finnish (FIN)

AF:

0.577

AC:

6094

AN:

10554

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.555

AC:

37662

AN:

67808

Other (OTH)

AF:

0.633

AC:

1339

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1642

3284

4926

6568

8210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.585

Hom.:

8674

Bravo

AF:

0.645

Asia WGS

AF:

0.624

AC:

2170

AN:

3478

EpiCase

AF:

0.572

EpiControl

AF:

0.577

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital hyperammonemia, type I (6)

not specified (6)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.2

(source)

DANN

Benign

0.69

PhyloP100

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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