2-210556606-G-A

Variant names:

• chr2-210556606-G-A
• rs182021022
• NM_001875.5:c.-128G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001875.5(CPS1):​c.-128G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00646 in 1,507,982 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (39 hom.)
• Consequence: CPS1 NM_001875.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15

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=-0.86).
• BP6: Variant 2-210556606-G-A is Benign according to our data. Variant chr2-210556606-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 334005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00472 (718/152032) while in subpopulation NFE AF = 0.00698 (474/67930). AF 95% confidence interval is 0.00646. There are 3 homozygotes in GnomAd4. There are 365 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.-128G>A		5_prime_UTR_variant	Exon 1 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.-128G>A		5_prime_UTR_variant	Exon 1 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 718 AN: 151914 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00414

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00698

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00666 AC: 9026 AN: 1355950 Hom.: 39 Cov.: 31 AF XY: 0.00645 AC XY: 4294 AN XY: 665838

African (AFR) AF: 0.000910 AC: 27 AN: 29660

American (AMR) AF: 0.00249 AC: 74 AN: 29698

Ashkenazi Jewish (ASJ) AF: 0.0000921 AC: 2 AN: 21704

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36046

South Asian (SAS) AF: 0.00439 AC: 309 AN: 70310

European-Finnish (FIN) AF: 0.0108 AC: 507 AN: 46862

Middle Eastern (MID) AF: 0.00126 AC: 6 AN: 4780

European-Non Finnish (NFE) AF: 0.00731 AC: 7757 AN: 1061154

Other (OTH) AF: 0.00615 AC: 343 AN: 55736

GnomAD4 genome AF: 0.00472 AC: 718 AN: 152032 Hom.: 3 Cov.: 32 AF XY: 0.00491 AC XY: 365 AN XY: 74336

African (AFR) AF: 0.00108 AC: 45 AN: 41504

American (AMR) AF: 0.00414 AC: 63 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0110 AC: 117 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00698 AC: 474 AN: 67930

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00598 Hom.: 1

Bravo AF: 0.00423

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 16, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital hyperammonemia, type I Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.21
DANN	Benign	0.38
PhyloP100		-1.2
PromoterAI		-0.0037	Neutral
Mutation Taster		=100/0	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: rs182021022; hg19: chr2-211421330; COSMIC: COSV99028199; COSMIC: COSV99028199;