2-210663103-GTTT-GTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 Benign/Likely_benign. ClinVar VariationId is 258483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	NM_001875.5	MANE Select	c.3928-8delT		splice_region intron	N/A	NP_001866.2
	CPS1	NM_001369256.1		c.3961-8delT		splice_region intron	N/A	NP_001356185.1
	CPS1	NM_001122633.3		c.3928-8delT		splice_region intron	N/A	NP_001116105.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.3928-19delT		intron	N/A	ENSP00000233072.5
	CPS1	ENST00000430249.7	TSL:1	c.3946-19delT		intron	N/A	ENSP00000402608.2
	CPS1	ENST00000451903.3	TSL:1	c.2575-19delT		intron	N/A	ENSP00000406136.2

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

GnomAD2 exomes AF: 0.689 AC: 123261 AN: 179012 AF XY: 0.686

Gnomad AFR exome AF: 0.625

Gnomad AMR exome AF: 0.652

Gnomad ASJ exome AF: 0.635

Gnomad EAS exome AF: 0.711

Gnomad FIN exome AF: 0.796

Gnomad NFE exome AF: 0.704

Gnomad OTH exome AF: 0.673

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

African (AFR) AF: 0.598 AC: 16602 AN: 27766

American (AMR) AF: 0.650 AC: 23816 AN: 36614

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 13527 AN: 20844

East Asian (EAS) AF: 0.701 AC: 21587 AN: 30774

South Asian (SAS) AF: 0.642 AC: 44984 AN: 70022

European-Finnish (FIN) AF: 0.738 AC: 30672 AN: 41536

Middle Eastern (MID) AF: 0.739 AC: 3585 AN: 4848

European-Non Finnish (NFE) AF: 0.685 AC: 584339 AN: 853258

Other (OTH) AF: 0.674 AC: 31612 AN: 46932

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

African (AFR) AF: 0.764 AC: 30916 AN: 40474

American (AMR) AF: 0.881 AC: 13052 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 3016 AN: 3448

East Asian (EAS) AF: 0.946 AC: 4814 AN: 5090

South Asian (SAS) AF: 0.894 AC: 4182 AN: 4680

European-Finnish (FIN) AF: 0.953 AC: 8588 AN: 9014

Middle Eastern (MID) AF: 0.860 AC: 246 AN: 286

European-Non Finnish (NFE) AF: 0.895 AC: 59901 AN: 66906

Other (OTH) AF: 0.857 AC: 1756 AN: 2050

Alfa AF: 0.695 Hom.: 2879

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

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.70
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: rs397703682; hg19: chr2-211527827;