Genetic Variant CPS1:c.4-321C>A (chr2-210556398-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369256.1(CPS1):c.19-321C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 499,874 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 55 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 23 hom. )

Consequence

CPS1
NM_001369256.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.39

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 2-210556398-C-A is Benign according to our data. Variant chr2-210556398-C-A is described in ClinVar as Benign. ClinVar VariationId is 1222196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369256.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
CPS1	NM_001369256.1	c.19-321C>A	intron	N/A	NP_001356185.1
CPS1	NM_001122633.3	c.-15-321C>A	intron	N/A	NP_001116105.2	P31327-1
CPS1	NM_001369257.1	c.-15-321C>A	intron	N/A	NP_001356186.1	P31327-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CPS1	ENST00000430249.7	TSL:1	c.4-321C>A	intron	N/A	ENSP00000402608.2	P31327-3
CPS1	ENST00000673510.1		c.-15-321C>A	intron	N/A	ENSP00000500537.1	P31327-1
CPS1	ENST00000673630.1		c.-15-321C>A	intron	N/A	ENSP00000501073.1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2326

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0535

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00499

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00317

AC:

405

AN:

127960

AF XY:

0.00251

show subpopulations

Gnomad AFR exome

AF:

0.0537

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000846

Gnomad OTH exome

AF:

0.00427

GnomAD4 exome

AF:

0.00204

AC:

709

AN:

347768

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

300

AN XY:

194808

show subpopulations

African (AFR)

AF:

0.0550

AC:

563

AN:

10230

American (AMR)

AF:

0.00274

AC:

AN:

28106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12268

East Asian (EAS)

AF:

0.00

AC:

AN:

11622

South Asian (SAS)

AF:

0.0000332

AC:

AN:

60274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13668

Middle Eastern (MID)

AF:

0.00167

AC:

AN:

2994

European-Non Finnish (NFE)

AF:

0.0000417

AC:

AN:

191788

Other (OTH)

AF:

0.00321

AC:

AN:

16818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0153

AC:

2330

AN:

152106

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1074

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0534

AC:

2219

AN:

41516

American (AMR)

AF:

0.00499

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67970

Other (OTH)

AF:

0.0118

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

108

216

323

431

539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0147

Hom.:

Bravo

AF:

0.0173

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

1.4

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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