rs140578009

Variant names:

• chr2-210674926-G-A
• rs140578009
• NM_001875.5:c.4126G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-210674926-G-A
• chr2-210674926-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001875.5(CPS1):​c.4126G>A​(p.Gly1376Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0136 in 1,613,610 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1376G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (31 hom., cov: 33)
  • Exomes 𝑓: 0.014 (174 hom.)
• Consequence: CPS1 NM_001875.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.38
• Publications: 24 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067127645).
• BP6: Variant 2-210674926-G-A is Benign according to our data. Variant chr2-210674926-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258484.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0127 (1939/152234) while in subpopulation AMR AF = 0.0158 (242/15282). AF 95% confidence interval is 0.0148. There are 31 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

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.4126G>A	p.Gly1376Ser	missense	Exon 35 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.4159G>A	p.Gly1387Ser	missense	Exon 36 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.4126G>A	p.Gly1376Ser	missense	Exon 36 of 39	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.4126G>A	p.Gly1376Ser	missense	Exon 35 of 38	ENSP00000233072.5	P31327-1
	CPS1	ENST00000430249.7	TSL:1	c.4144G>A	p.Gly1382Ser	missense	Exon 36 of 39	ENSP00000402608.2	P31327-3
	CPS1	ENST00000451903.3	TSL:1	c.2773G>A	p.Gly925Ser	missense	Exon 25 of 28	ENSP00000406136.2	P31327-2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152116 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0131 AC: 3283 AN: 251254 AF XY: 0.0132

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0137 AC: 20051 AN: 1461376 Hom.: 174 Cov.: 29 AF XY: 0.0136 AC XY: 9875 AN XY: 727016

African (AFR) AF: 0.00263 AC: 88 AN: 33472

American (AMR) AF: 0.0125 AC: 561 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 795 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00473 AC: 408 AN: 86246

European-Finnish (FIN) AF: 0.0315 AC: 1683 AN: 53402

Middle Eastern (MID) AF: 0.0361 AC: 208 AN: 5758

European-Non Finnish (NFE) AF: 0.0139 AC: 15419 AN: 1111612

Other (OTH) AF: 0.0147 AC: 889 AN: 60370

GnomAD4 genome AF: 0.0127 AC: 1939 AN: 152234 Hom.: 31 Cov.: 33 AF XY: 0.0132 AC XY: 984 AN XY: 74438

African (AFR) AF: 0.00291 AC: 121 AN: 41542

American (AMR) AF: 0.0158 AC: 242 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 123 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4822

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1063 AN: 68012

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.0139 Hom.: 33

Bravo AF: 0.0108

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.0118 AC: 1430

EpiCase AF: 0.0175

EpiControl AF: 0.0176

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Congenital hyperammonemia, type I (4)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.036
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.57	N
PhyloP100		4.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.28
Sift	Benign	0.19	T
Sift4G	Benign	0.24	T
Polyphen		0.0070	B
Vest4		0.074
MPC		0.23
ClinPred		0.0090	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.51
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140578009; hg19: chr2-211539650; COSMIC: COSV51818882;