2-210608346-G-T

Variant names:

Variant summary

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

The NM_001875.5(CPS1):c.2193-15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,608,256 control chromosomes in the GnomAD database, including 13,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 999 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12439 hom. )

Consequence

CPS1
NM_001875.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.141

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-210608346-G-T is Benign according to our data. Variant chr2-210608346-G-T is described in ClinVar as Benign. ClinVar VariationId is 137023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5 link	c.2193-15G>T		intron_variant	Intron 18 of 37	ENST00000233072.10	NP_001866.2	P31327-1A0A024R454Q6PEK7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 link	c.2193-15G>T		intron_variant	Intron 18 of 37	1	NM_001875.5	ENSP00000233072.5		P31327-1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15515

AN:

151782

Hom.:

996

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0364

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.138

Gnomad EAS

AF:

0.263

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.102

GnomAD2 exomes

AF:

0.127

AC:

31517

AN:

249112

AF XY:

0.127

show subpopulations

Gnomad AFR exome

AF:

0.0349

Gnomad AMR exome

AF:

0.133

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.236

Gnomad FIN exome

AF:

0.117

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.125

AC:

182204

AN:

1456356

Hom.:

12439

Cov.:

AF XY:

0.126

AC XY:

91408

AN XY:

724766

show subpopulations

African (AFR)

AF:

0.0328

AC:

1093

AN:

33286

American (AMR)

AF:

0.133

AC:

5914

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

3512

AN:

25980

East Asian (EAS)

AF:

0.291

AC:

11513

AN:

39610

South Asian (SAS)

AF:

0.132

AC:

11401

AN:

86096

European-Finnish (FIN)

AF:

0.113

AC:

6016

AN:

53024

Middle Eastern (MID)

AF:

0.0817

AC:

469

AN:

5744

European-Non Finnish (NFE)

AF:

0.121

AC:

134445

AN:

1108004

Other (OTH)

AF:

0.130

AC:

7841

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

7011

14022

21032

28043

35054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5002

10004

15006

20008

25010

<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:

0.102

AC:

15515

AN:

151900

Hom.:

999

Cov.:

AF XY:

0.104

AC XY:

7741

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.0363

AC:

1508

AN:

41504

American (AMR)

AF:

0.133

AC:

2020

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

479

AN:

3464

East Asian (EAS)

AF:

0.263

AC:

1343

AN:

5112

South Asian (SAS)

AF:

0.144

AC:

694

AN:

4822

European-Finnish (FIN)

AF:

0.114

AC:

1211

AN:

10594

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

7977

AN:

67852

Other (OTH)

AF:

0.106

AC:

223

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

716

1433

2149

2866

3582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.0781

Hom.:

139

Bravo

AF:

0.0979

Asia WGS

AF:

0.237

AC:

822

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Congenital hyperammonemia, type I

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c. c.2193-15G>T in CPS1 gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this do not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.1255 (14937 / 119028 chrs tested), across multiple ethnicities, including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0015%, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign by several reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.23

(source)

DANN

Benign

0.39

PhyloP100

-0.14

Mutation Taster

=19/81

disease causing (long InDel)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over