2-210678331-T-C

Variant names:

• chr2-210678331-T-C
• rs715
• ENST00000479988.1:n.4035T>C

Variant summary

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

The ENST00000479988.1(CPS1):​n.4035T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 355,210 control chromosomes in the GnomAD database, including 15,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6148 hom., cov: 32)
  • Exomes 𝑓: 0.30 (9181 hom.)
• Consequence: CPS1 ENST00000479988.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.83
• Publications: 108 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-210678331-T-C is Benign according to our data. Variant chr2-210678331-T-C is described in ClinVar as Benign. ClinVar VariationId is 334042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.*346T>C		3_prime_UTR_variant	Exon 38 of 38	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.*346T>C		3_prime_UTR_variant	Exon 38 of 38	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42453 AN: 151988 Hom.: 6142 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.297 AC: 60254 AN: 203104 Hom.: 9181 Cov.: 0 AF XY: 0.298 AC XY: 32906 AN XY: 110454

African (AFR) AF: 0.211 AC: 1234 AN: 5858

American (AMR) AF: 0.295 AC: 2456 AN: 8318

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1753 AN: 5318

East Asian (EAS) AF: 0.192 AC: 1772 AN: 9240

South Asian (SAS) AF: 0.296 AC: 10491 AN: 35488

European-Finnish (FIN) AF: 0.323 AC: 2920 AN: 9028

Middle Eastern (MID) AF: 0.298 AC: 222 AN: 746

European-Non Finnish (NFE) AF: 0.306 AC: 36342 AN: 118700

Other (OTH) AF: 0.294 AC: 3064 AN: 10408

GnomAD4 genome AF: 0.279 AC: 42473 AN: 152106 Hom.: 6148 Cov.: 32 AF XY: 0.280 AC XY: 20855 AN XY: 74360

African (AFR) AF: 0.206 AC: 8546 AN: 41520

American (AMR) AF: 0.295 AC: 4501 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1122 AN: 3468

East Asian (EAS) AF: 0.175 AC: 903 AN: 5160

South Asian (SAS) AF: 0.298 AC: 1438 AN: 4828

European-Finnish (FIN) AF: 0.345 AC: 3650 AN: 10570

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21324 AN: 67974

Other (OTH) AF: 0.283 AC: 597 AN: 2108

Alfa AF: 0.295 Hom.: 14624

Bravo AF: 0.273

Asia WGS AF: 0.239 AC: 834 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.63
PhyloP100		2.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs715; hg19: chr2-211543055;