2-210556540-G-A

Variant names:

• chr2-210556540-G-A
• rs6732642
• ENST00000430249.7:c.4-179G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369256.1(CPS1):​c.19-179G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,474,476 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (92 hom.)
• Consequence: CPS1 NM_001369256.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.86

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-210556540-G-A is Benign according to our data. Variant chr2-210556540-G-A is described in ClinVar as [Benign]. Clinvar id is 1297986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.-194G>A		upstream_gene_variant		ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.-194G>A		upstream_gene_variant		1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3134 AN: 151920 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00776

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00217 AC: 2874 AN: 1322438 Hom.: 92 Cov.: 26 AF XY: 0.00191 AC XY: 1237 AN XY: 648912

African (AFR) AF: 0.0793 AC: 2320 AN: 29274

American (AMR) AF: 0.00445 AC: 127 AN: 28566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21266

East Asian (EAS) AF: 0.00 AC: 0 AN: 34740

South Asian (SAS) AF: 0.000290 AC: 20 AN: 68884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36862

Middle Eastern (MID) AF: 0.00487 AC: 24 AN: 4924

European-Non Finnish (NFE) AF: 0.0000863 AC: 90 AN: 1043208

Other (OTH) AF: 0.00536 AC: 293 AN: 54714

GnomAD4 genome AF: 0.0206 AC: 3138 AN: 152038 Hom.: 94 Cov.: 32 AF XY: 0.0202 AC XY: 1503 AN XY: 74312

African (AFR) AF: 0.0714 AC: 2962 AN: 41484

American (AMR) AF: 0.00768 AC: 117 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67974

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0258 Hom.: 14

Bravo AF: 0.0239

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.77
PhyloP100		1.9
PromoterAI		0.057	Neutral
Mutation Taster		=299/1	polymorphism

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

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Other links and lift over

dbSNP: rs6732642; hg19: chr2-211421264;