chr2-210556705-T-G

Position:

chr2-210556705-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000430249.7(CPS1):c.4-14T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,601,440 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 9 hom., cov: 32)

Exomes 𝑓: 0.010 ( 127 hom. )

Consequence

CPS1
ENST00000430249.7 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.494

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-210556705-T-G is Benign according to our data. Variant chr2-210556705-T-G is described in ClinVar as [Benign]. Clinvar id is 334007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210556705-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00891 (1272/142758) while in subpopulation SAS AF= 0.0236 (103/4364). AF 95% confidence interval is 0.0199. There are 9 homozygotes in gnomad4. There are 662 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001875.5 linkuse as main transcript	c.-29T>G		5_prime_UTR_variant	1/38	ENST00000233072.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.-29T>G		5_prime_UTR_variant	1/38	1	NM_001875.5	P1	P31327-1

Frequencies

GnomAD3 genomes

AF:

0.00892

AC:

1272

AN:

142668

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0235

Gnomad FIN

AF:

0.00973

Gnomad MID

AF:

0.0205

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0135

GnomAD3 exomes

AF:

0.0116

AC:

2858

AN:

246558

Hom.:

AF XY:

0.0128

AC XY:

1707

AN XY:

133622

show subpopulations

Gnomad AFR exome

AF:

0.000832

Gnomad AMR exome

AF:

0.00628

Gnomad ASJ exome

AF:

0.0273

Gnomad EAS exome

AF:

0.000330

Gnomad SAS exome

AF:

0.0258

Gnomad FIN exome

AF:

0.0112

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0104

AC:

15157

AN:

1458682

Hom.:

127

Cov.:

AF XY:

0.0109

AC XY:

7908

AN XY:

725710

show subpopulations

Gnomad4 AFR exome

AF:

0.000902

Gnomad4 AMR exome

AF:

0.00632

Gnomad4 ASJ exome

AF:

0.0275

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0246

Gnomad4 FIN exome

AF:

0.0122

Gnomad4 NFE exome

AF:

0.00959

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.00891

AC:

1272

AN:

142758

Hom.:

Cov.:

AF XY:

0.00952

AC XY:

662

AN XY:

69508

show subpopulations

Gnomad4 AFR

AF:

0.00181

Gnomad4 AMR

AF:

0.0140

Gnomad4 ASJ

AF:

0.0308

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0236

Gnomad4 FIN

AF:

0.00973

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.0134

Alfa

AF:

0.0111

Hom.:

Bravo

AF:

0.00691

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2016

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. -

CPS1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital hyperammonemia, type I

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.8

DANN

Benign

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over