chr2-210650334-A-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.3405-29A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,580,844 control chromosomes in the GnomAD database, including 133,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.38 ( 11787 hom., cov: 32)

Exomes 𝑓: 0.41 ( 121790 hom. )

Consequence

CPS1
NM_001875.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 2.81

Publications

14 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

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-210650334-A-T is Benign according to our data. Variant chr2-210650334-A-T is described in ClinVar as Benign. ClinVar VariationId is 258479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5 link	c.3405-29A>T		intron_variant	Intron 27 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 link	c.3405-29A>T		intron_variant	Intron 27 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes

AF:

0.384

AC:

58362

AN:

151796

Hom.:

11785

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.340

Gnomad AMR

AF:

0.467

Gnomad ASJ

AF:

0.333

Gnomad EAS

AF:

0.521

Gnomad SAS

AF:

0.421

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.397

GnomAD2 exomes

AF:

0.425

AC:

106621

AN:

250998

AF XY:

0.423

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.503

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.520

Gnomad FIN exome

AF:

0.480

Gnomad NFE exome

AF:

0.407

Gnomad OTH exome

AF:

0.410

GnomAD4 exome

AF:

0.410

AC:

585457

AN:

1428928

Hom.:

121790

Cov.:

AF XY:

0.408

AC XY:

291302

AN XY:

713138

show subpopulations

African (AFR)

AF:

0.263

AC:

8635

AN:

32798

American (AMR)

AF:

0.502

AC:

22378

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

8821

AN:

25920

East Asian (EAS)

AF:

0.499

AC:

19695

AN:

39496

South Asian (SAS)

AF:

0.414

AC:

35452

AN:

85570

European-Finnish (FIN)

AF:

0.479

AC:

25529

AN:

53352

Middle Eastern (MID)

AF:

0.289

AC:

1650

AN:

5712

European-Non Finnish (NFE)

AF:

0.406

AC:

439527

AN:

1082278

Other (OTH)

AF:

0.401

AC:

23770

AN:

59208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

17782

35564

53347

71129

88911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13444

26888

40332

53776

67220

<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:

0.384

AC:

58395

AN:

151916

Hom.:

11787

Cov.:

AF XY:

0.389

AC XY:

28906

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.270

AC:

11186

AN:

41458

American (AMR)

AF:

0.467

AC:

7125

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

1153

AN:

3464

East Asian (EAS)

AF:

0.521

AC:

2679

AN:

5144

South Asian (SAS)

AF:

0.421

AC:

2027

AN:

4814

European-Finnish (FIN)

AF:

0.481

AC:

5082

AN:

10556

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.411

AC:

27916

AN:

67908

Other (OTH)

AF:

0.395

AC:

834

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1796

3592

5389

7185

8981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

564

1128

1692

2256

2820

<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:

0.387

Hom.:

2126

Bravo

AF:

0.378

Asia WGS

AF:

0.456

AC:

1584

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Jun 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital hyperammonemia, type I

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.60

PhyloP100

2.8

La Branchor

0.84

BranchPoint Hunter

5.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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