Genetic Variant CPS1:c.3928-8dupT (chr2-210663103-G-GT) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001875.5(CPS1):c.3928-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000068 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

CPS1
NM_001875.5 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.697

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 2-210663103-G-GT is Benign according to our data. Variant chr2-210663103-G-GT is described in ClinVar as Likely_benign. ClinVar VariationId is 2183375.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3928-8dupT	splice_region intron	N/A	NP_001866.2
CPS1	NM_001369256.1		c.3961-8dupT	splice_region intron	N/A	NP_001356185.1
CPS1	NM_001122633.3		c.3928-8dupT	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.3928-20_3928-19insT	intron	N/A	ENSP00000233072.5
CPS1	ENST00000430249.7	TSL:1	c.3946-20_3946-19insT	intron	N/A	ENSP00000402608.2
CPS1	ENST00000451903.3	TSL:1	c.2575-20_2575-19insT	intron	N/A	ENSP00000406136.2

Frequencies

GnomAD3 genomes

AF:

0.0000677

AC:

AN:

147640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000448

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000978

AC:

175

AN:

179012

AF XY:

0.000918

show subpopulations

Gnomad AFR exome

AF:

0.00248

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.000646

Gnomad EAS exome

AF:

0.000553

Gnomad FIN exome

AF:

0.0000658

Gnomad NFE exome

AF:

0.000698

Gnomad OTH exome

AF:

0.000457

GnomAD4 exome

AF:

0.00152

AC:

1719

AN:

1128336

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

825

AN XY:

564638

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00413

AC:

114

AN:

27624

American (AMR)

AF:

0.00195

AC:

AN:

36488

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

20768

East Asian (EAS)

AF:

0.000358

AC:

AN:

30740

South Asian (SAS)

AF:

0.00142

AC:

AN:

69692

European-Finnish (FIN)

AF:

0.0000964

AC:

AN:

41504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4840

European-Non Finnish (NFE)

AF:

0.00156

AC:

1328

AN:

849954

Other (OTH)

AF:

0.00131

AC:

AN:

46726

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

213

426

640

853

1066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<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:

0.0000677

AC:

AN:

147640

Hom.:

Cov.:

AF XY:

0.0000696

AC XY:

AN XY:

71802

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

40402

American (AMR)

AF:

0.00

AC:

AN:

14808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.000196

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

66920

Other (OTH)

AF:

0.00

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00372

Hom.:

2879

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Benign:1

Apr 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.70

Mutation Taster

=100/0

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

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

2-210663103-GTTT-GTTTT

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over