chr2-210556738-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001875.5(CPS1):​c.5C>T​(p.Thr2Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,611,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

CPS1
NM_001875.5 missense

Scores

1
9
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2185871).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CPS1NM_001875.5 linkuse as main transcriptc.5C>T p.Thr2Met missense_variant 1/38 ENST00000233072.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CPS1ENST00000233072.10 linkuse as main transcriptc.5C>T p.Thr2Met missense_variant 1/381 NM_001875.5 P1P31327-1

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
151676
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000267
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000329
Gnomad ASJ
AF:
0.000866
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000190
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000883
Gnomad OTH
AF:
0.000960
GnomAD3 exomes
AF:
0.000148
AC:
37
AN:
250764
Hom.:
0
AF XY:
0.000148
AC XY:
20
AN XY:
135518
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.000204
Gnomad ASJ exome
AF:
0.000995
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000925
Gnomad NFE exome
AF:
0.0000617
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.0000849
AC:
124
AN:
1460322
Hom.:
0
Cov.:
32
AF XY:
0.0000840
AC XY:
61
AN XY:
726444
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.000292
Gnomad4 ASJ exome
AF:
0.000959
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000191
AC:
29
AN:
151676
Hom.:
0
Cov.:
32
AF XY:
0.000203
AC XY:
15
AN XY:
74032
show subpopulations
Gnomad4 AFR
AF:
0.000267
Gnomad4 AMR
AF:
0.000329
Gnomad4 ASJ
AF:
0.000866
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000190
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.000960
Alfa
AF:
0.000144
Hom.:
0
Bravo
AF:
0.000317
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 10, 2021The c.5C>T (p.T2M) alteration is located in exon 1 (coding exon 1) of the CPS1 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the threonine (T) at amino acid position 2 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 02, 2021The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.071
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.014
T;T;T;.;T;T
Eigen
Benign
-0.12
Eigen_PC
Benign
0.062
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.86
.;D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.22
T;T;T;T;T;T
MetaSVM
Uncertain
0.53
D
MutationAssessor
Benign
0.97
.;.;.;.;L;.
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.68
N;N;N;N;N;.
REVEL
Uncertain
0.42
Sift
Uncertain
0.025
D;D;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;T;D;D
Polyphen
0.076
.;.;.;.;B;.
Vest4
0.30, 0.21, 0.28
MVP
0.94
MPC
0.81
ClinPred
0.061
T
GERP RS
4.9
Varity_R
0.063
gMVP
0.63

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.

Other links and lift over

dbSNP: rs150314086; hg19: chr2-211421462; API