2-210477765-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000430249.7(CPS1):c.2T>G(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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CPS1 ENST00000430249.7 start_lost, splice_region
• Scores: Splicing: ADA: 0.0005495
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.170

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPS1	NM_001122633.3	c.-17T>G		splice_region_variant, 5_prime_UTR_variant	1/39
CPS1	NM_001369257.1	c.-137T>G		splice_region_variant, 5_prime_UTR_variant	1/40

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPS1	ENST00000430249.7	c.2T>G	p.Met1?	start_lost, splice_region_variant	1/39	1
CPS1	ENST00000673510.1	c.-137T>G		splice_region_variant, 5_prime_UTR_variant	1/40			P1
CPS1	ENST00000673630.1	c.-251T>G		splice_region_variant, 5_prime_UTR_variant	1/40			P1
CPS1	ENST00000673711.1	c.-17T>G		splice_region_variant, 5_prime_UTR_variant	1/39			P1

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

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

Submissions by phenotype

Congenital hyperammonemia, type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 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

Other links and lift over

dbSNP: rs763703546; hg19: chr2-211342489;