chr2-210477765-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000430249.7(CPS1):ā€‹c.2T>Gā€‹(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

CPS1
ENST00000430249.7 start_lost, splice_region

Scores

2
3
10
Splicing: ADA: 0.0005495
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.170
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CPS1NM_001122633.3 linkuse as main transcriptc.-17T>G splice_region_variant, 5_prime_UTR_variant 1/39
CPS1NM_001369257.1 linkuse as main transcriptc.-137T>G splice_region_variant, 5_prime_UTR_variant 1/40

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CPS1ENST00000430249.7 linkuse as main transcriptc.2T>G p.Met1? start_lost, splice_region_variant 1/391 P31327-3
CPS1ENST00000673510.1 linkuse as main transcriptc.-137T>G splice_region_variant, 5_prime_UTR_variant 1/40 P1P31327-1
CPS1ENST00000673630.1 linkuse as main transcriptc.-251T>G splice_region_variant, 5_prime_UTR_variant 1/40 P1P31327-1
CPS1ENST00000673711.1 linkuse as main transcriptc.-17T>G splice_region_variant, 5_prime_UTR_variant 1/39 P1P31327-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461230
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726882
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital hyperammonemia, type I Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylDec 04, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.085
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
3.3
DANN
Benign
0.78
DEOGEN2
Benign
0.0060
T;.
Eigen
Benign
0.014
Eigen_PC
Benign
-0.42
FATHMM_MKL
Benign
0.056
N
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.014
T
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
0.34
D
MutationTaster
Benign
1.0
N
PROVEAN
Benign
-0.45
N;N
REVEL
Benign
0.23
Sift
Pathogenic
0.0
D;D
Vest4
0.22
MutPred
0.99
Gain of MoRF binding (P = 0.0526);Gain of MoRF binding (P = 0.0526);
MVP
0.95
ClinPred
0.037
T
GERP RS
-0.55
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00055
dbscSNV1_RF
Benign
0.024

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: rs763703546; hg19: chr2-211342489; API