2-210674926-G-C

Variant names:

• chr2-210674926-G-C
• NM_001875.5:c.4126G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001875.5(CPS1):​c.4126G>C​(p.Gly1376Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. G1376S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.38

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain MGS-like (size 145) in uniprot entity CPSM_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_001875.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36031026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.4126G>C	p.Gly1376Arg	missense_variant	Exon 35 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.4126G>C	p.Gly1376Arg	missense_variant	Exon 35 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461584 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 727098

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.90	.;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.089	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.55	.;P;.
Vest4		0.48
MutPred		0.38		.;Gain of MoRF binding (P = 0.0415);.;
MVP		0.84
MPC		0.48
ClinPred		0.60	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-211539650;