chr2-210650334-A-T

Variant names:

• chr2-210650334-A-T
• rs3213784
• NM_001875.5:c.3405-29A>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001875.5(CPS1):​c.3405-29A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,580,844 control chromosomes in the GnomAD database, including 133,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.38 (11787 hom., cov: 32)
  • Exomes 𝑓: 0.41 (121790 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 2.81

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 Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-210650334-A-T is Benign according to our data. Variant chr2-210650334-A-T is described in ClinVar as [Benign]. Clinvar id is 258479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210650334-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.3405-29A>T		intron_variant	Intron 27 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.3405-29A>T		intron_variant	Intron 27 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58362 AN: 151796 Hom.: 11785 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.397

GnomAD3 exomes AF: 0.425 AC: 106621 AN: 250998 Hom.: 23377 AF XY: 0.423 AC XY: 57456 AN XY: 135682

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.503

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.520

Gnomad SAS exome AF: 0.421

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.410 AC: 585457 AN: 1428928 Hom.: 121790 Cov.: 27 AF XY: 0.408 AC XY: 291302 AN XY: 713138

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.340

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.414

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.406

Gnomad4 OTH exome AF: 0.401

GnomAD4 genome AF: 0.384 AC: 58395 AN: 151916 Hom.: 11787 Cov.: 32 AF XY: 0.389 AC XY: 28906 AN XY: 74262

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.467

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.521

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.395

Alfa AF: 0.387 Hom.: 2126

Bravo AF: 0.378

Asia WGS AF: 0.456 AC: 1584 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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not specified Benign:1

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Congenital hyperammonemia, type I Benign:1

Jul 10, 2021

Genome-Nilou Lab

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	-0.79
CADD	Benign	17
DANN	Benign	0.60
La Branchor		0.84
BranchPoint Hunter		5.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs3213784; hg19: chr2-211515058; COSMIC: COSV51811843; COSMIC: COSV51811843;