dbSNP rs201058019: CPS1:c.2192+6A>T (chr2-210606947-A-T) – 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.2192+6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,609,774 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

CPS1
NM_001875.5 splice_region, intron

Scores

Splicing: ADA: 0.0001026

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.820

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

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 (BayesDel_noAF=-0.75).

BP6

Variant 2-210606947-A-T is Benign according to our data. Variant chr2-210606947-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334025.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000763 (116/152110) while in subpopulation NFE AF = 0.00152 (103/67906). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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	Effect	Exon Rank	Protein
CPS1	NM_001875.5	MANE Select	c.2192+6A>T	splice_region intron	N/A	NP_001866.2
CPS1	NM_001369256.1		c.2225+6A>T	splice_region intron	N/A	NP_001356185.1
CPS1	NM_001122633.3		c.2192+6A>T	splice_region intron	N/A	NP_001116105.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CPS1	ENST00000233072.10	TSL:1 MANE Select	c.2192+6A>T	splice_region intron	N/A	ENSP00000233072.5
CPS1	ENST00000430249.7	TSL:1	c.2210+6A>T	splice_region intron	N/A	ENSP00000402608.2
CPS1	ENST00000451903.3	TSL:1	c.839+6A>T	splice_region intron	N/A	ENSP00000406136.2

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

116

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00152

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000565

AC:

141

AN:

249456

AF XY:

0.000593

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.00128

AC:

1859

AN:

1457664

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

950

AN XY:

724950

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33326

American (AMR)

AF:

0.00

AC:

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.00

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5448

European-Non Finnish (NFE)

AF:

0.00162

AC:

1800

AN:

1109156

Other (OTH)

AF:

0.000848

AC:

AN:

60140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

168

251

335

419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<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:

0.000763

AC:

116

AN:

152110

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41558

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00152

AC:

103

AN:

67906

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000672

EpiCase

AF:

0.000874

EpiControl

AF:

0.000831

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital hyperammonemia, type I (3)

CPS1-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

9.6

(source)

DANN

Benign

0.50

PhyloP100

0.82

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.0080

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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