2-210663103-GTTT-GTT

Variant names:

• chr2-210663103-GT-G
• rs397703682
• NM_001875.5:c.3928-8delT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001875.5(CPS1):​c.3928-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (55074 hom., cov: 0)
  • Exomes 𝑓: 0.68 (210415 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPS1 NM_001875.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.697

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 -16 ACMG points.

• BP6: Variant 2-210663103-GT-G is Benign according to our data. Variant chr2-210663103-GT-G is described in ClinVar as [Likely_benign]. Clinvar id is 258483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210663103-GT-G is described in Lovd as [Likely_benign]. Variant chr2-210663103-GT-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.3928-8delT		splice_region_variant, intron_variant	Intron 32 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.3928-19delT		intron_variant	Intron 32 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes AF: 0.862 AC: 127219 AN: 147598 Hom.: 55043 Cov.: 0

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.953

Gnomad MID AF: 0.860

Gnomad NFE AF: 0.895

Gnomad OTH AF: 0.855

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.680 AC: 770724 AN: 1132594 Hom.: 210415 Cov.: 0 AF XY: 0.679 AC XY: 384943 AN XY: 566710

Gnomad4 AFR exome AF: 0.598

Gnomad4 AMR exome AF: 0.650

Gnomad4 ASJ exome AF: 0.649

Gnomad4 EAS exome AF: 0.701

Gnomad4 SAS exome AF: 0.642

Gnomad4 FIN exome AF: 0.738

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.674

GnomAD4 genome AF: 0.862 AC: 127279 AN: 147674 Hom.: 55074 Cov.: 0 AF XY: 0.867 AC XY: 62293 AN XY: 71860

Gnomad4 AFR AF: 0.764

Gnomad4 AMR AF: 0.881

Gnomad4 ASJ AF: 0.875

Gnomad4 EAS AF: 0.946

Gnomad4 SAS AF: 0.894

Gnomad4 FIN AF: 0.953

Gnomad4 NFE AF: 0.895

Gnomad4 OTH AF: 0.857

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hyperammonemia, type I Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Sep 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pulmonary hypertension, neonatal, susceptibility to;C4082171:Congenital hyperammonemia, type I Benign:1

May 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs397703682; hg19: chr2-211527827;