2-210608431-TC-AG

Variant names:

• chr2-210608431-TC-AG
• NM_001875.5:c.2263_2264delTCinsAG
• CPS1 p.756

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001875.5(CPS1):​c.2263_2264delTCinsAG​(p.756) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S755S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPS1 NM_001875.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	NM_001875.5	MANE Select	c.2263_2264delTCinsAG	p.756	synonymous	N/A	NP_001866.2
	CPS1	NM_001369256.1		c.2296_2297delTCinsAG	p.767	synonymous	N/A	NP_001356185.1
	CPS1	NM_001122633.3		c.2263_2264delTCinsAG	p.756	synonymous	N/A	NP_001116105.2	P31327-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.2263_2264delTCinsAG	p.756	synonymous	N/A	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.2281_2282delTCinsAG	p.762	synonymous	N/A	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.910_911delTCinsAG	p.305	synonymous	N/A	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-211473155;