2-210674926-G-A

Position:

chr2-210674926-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001875.5(CPS1):c.4126G>A(p.Gly1376Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0136 in 1,613,610 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 31 hom., cov: 33)

Exomes 𝑓: 0.014 ( 174 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.38

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:

CPS1 (HGNC:):

CPS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a domain MGS-like (size 145) in uniprot entity CPSM_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_001875.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0067127645).

BP6

Variant 2-210674926-G-A is Benign according to our data. Variant chr2-210674926-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258484.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr2-210674926-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0127 (1939/152234) while in subpopulation AMR AF= 0.0158 (242/15282). AF 95% confidence interval is 0.0148. There are 31 homozygotes in gnomad4. There are 984 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001875.5 linkuse as main transcript	c.4126G>A	p.Gly1376Ser	missense_variant	35/38	ENST00000233072.10	NP_001866.2	P31327-1A0A024R454Q6PEK7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10 linkuse as main transcript	c.4126G>A	p.Gly1376Ser	missense_variant	35/38	1	NM_001875.5	ENSP00000233072.5		P31327-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1936

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.0293

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.0131

AC:

3283

AN:

251254

Hom.:

AF XY:

0.0132

AC XY:

1794

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0299

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00425

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0245

GnomAD4 exome

AF:

0.0137

AC:

20051

AN:

1461376

Hom.:

174

Cov.:

AF XY:

0.0136

AC XY:

9875

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.00263

Gnomad4 AMR exome

AF:

0.0125

Gnomad4 ASJ exome

AF:

0.0304

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00473

Gnomad4 FIN exome

AF:

0.0315

Gnomad4 NFE exome

AF:

0.0139

Gnomad4 OTH exome

AF:

0.0147

GnomAD4 genome

AF:

0.0127

AC:

1939

AN:

152234

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

984

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.0354

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00664

Gnomad4 FIN

AF:

0.0293

Gnomad4 NFE

AF:

0.0156

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0118

AC:

1430

EpiCase

AF:

0.0175

EpiControl

AF:

0.0176

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

CPS1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;T;.

Eigen

Benign

0.036

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;D;D

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.57

.;N;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.64

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.0070

.;B;.

Vest4

0.074

MPC

0.23

ClinPred

0.0090

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.51

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

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