Genetic Variant CPS1:c.4-338G>T (chr2-210556381-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001369256.1(CPS1):c.19-338G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 479,756 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 8 hom. )

Consequence

CPS1
NM_001369256.1 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.17

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=-0.81).

BP6

Variant 2-210556381-G-T is Benign according to our data. Variant chr2-210556381-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1205371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1870/152126) while in subpopulation AFR AF = 0.042 (1744/41520). AF 95% confidence interval is 0.0404. There are 33 homozygotes in GnomAd4. There are 851 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

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.19-338G>T	intron	N/A	NP_001356185.1
CPS1	NM_001122633.3	c.-15-338G>T	intron	N/A	NP_001116105.2	P31327-1
CPS1	NM_001369257.1	c.-15-338G>T	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.4-338G>T	intron	N/A	ENSP00000402608.2	P31327-3
CPS1	ENST00000673510.1		c.-15-338G>T	intron	N/A	ENSP00000500537.1	P31327-1
CPS1	ENST00000673630.1		c.-15-338G>T	intron	N/A	ENSP00000501073.1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1862

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0419

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00637

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00254

AC:

325

AN:

128000

AF XY:

0.00211

show subpopulations

Gnomad AFR exome

AF:

0.0421

Gnomad AMR exome

AF:

0.00222

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00176

GnomAD4 exome

AF:

0.00165

AC:

542

AN:

327630

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

231

AN XY:

184888

show subpopulations

African (AFR)

AF:

0.0412

AC:

392

AN:

9508

American (AMR)

AF:

0.00241

AC:

AN:

27752

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11688

East Asian (EAS)

AF:

0.00

AC:

AN:

10534

South Asian (SAS)

AF:

0.000117

AC:

AN:

59998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13134

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

2882

European-Non Finnish (NFE)

AF:

0.000125

AC:

AN:

176402

Other (OTH)

AF:

0.00318

AC:

AN:

15732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

108

135

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:

0.0123

AC:

1870

AN:

152126

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

851

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0420

AC:

1744

AN:

41520

American (AMR)

AF:

0.00636

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67976

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

190

285

380

475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00594

Hom.:

Bravo

AF:

0.0139

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely 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

-0.81

CADD

Benign

5.7

(source)

DANN

Benign

0.57

PhyloP100

1.2

PromoterAI

-0.0039

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