2-210663175-G-T

Variant names:

• chr2-210663175-G-T
• rs1553518389
• NM_001875.5:c.3980G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001875.5(CPS1):​c.3980G>T​(p.Cys1327Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1327Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.52
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• carbamoyl phosphate synthetase I deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-210663175-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 488489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.3980G>T	p.Cys1327Phe	missense_variant	Exon 33 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.3980G>T	p.Cys1327Phe	missense_variant	Exon 33 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	1.8	.;L;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.98	.;D;.
Vest4		0.93
MutPred		0.64		.;Gain of loop (P = 0.069);.;
MVP		0.96
MPC		1.0
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.94
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs1553518389; hg19: chr2-211527899;