rs61509952

Variant names:

• chr2-210556728-A-ATCT
• rs61509952
• ENST00000430249.7:c.15_16insTTC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_001369256.1(CPS1):​c.30_31insTTC​(p.Ile10_Lys11insPhe) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,610,000 control chromosomes in the GnomAD database, including 135,416 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16844 hom., cov: 0)
  • Exomes 𝑓: 0.40 (118572 hom.)
• Consequence: CPS1 NM_001369256.1 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.503
• Publications: 6 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001369256.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-210556728-A-ATCT is Benign according to our data. Variant chr2-210556728-A-ATCT is described in ClinVar as Benign. ClinVar VariationId is 203647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369256.1. 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.-4_-3insTTC		5_prime_UTR	Exon 1 of 38	NP_001866.2
	CPS1	NM_001369256.1		c.30_31insTTC	p.Ile10_Lys11insPhe	conservative_inframe_insertion	Exon 2 of 39	NP_001356185.1
	CPS1	NM_001122633.3		c.-4_-3insTTC		5_prime_UTR	Exon 2 of 39	NP_001116105.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPS1	ENST00000430249.7	TSL:1	c.15_16insTTC	p.Ile5_Lys6insPhe	conservative_inframe_insertion	Exon 2 of 39	ENSP00000402608.2
	CPS1	ENST00000233072.10	TSL:1 MANE Select	c.-4_-3insTTC		5_prime_UTR	Exon 1 of 38	ENSP00000233072.5
	CPS1	ENST00000881564.1		c.-4_-3insTTC		5_prime_UTR	Exon 1 of 38	ENSP00000551623.1

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70024 AN: 151426 Hom.: 16788 Cov.: 0

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.438 AC: 109431 AN: 250072 AF XY: 0.435

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.521

Gnomad ASJ exome AF: 0.446

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.425

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.399 AC: 581701 AN: 1458456 Hom.: 118572 Cov.: 32 AF XY: 0.401 AC XY: 291067 AN XY: 725582

African (AFR) AF: 0.595 AC: 19858 AN: 33350

American (AMR) AF: 0.522 AC: 23250 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 11485 AN: 26046

East Asian (EAS) AF: 0.345 AC: 13667 AN: 39652

South Asian (SAS) AF: 0.463 AC: 39900 AN: 86094

European-Finnish (FIN) AF: 0.420 AC: 22434 AN: 53384

Middle Eastern (MID) AF: 0.570 AC: 3281 AN: 5758

European-Non Finnish (NFE) AF: 0.381 AC: 422259 AN: 1109386

Other (OTH) AF: 0.424 AC: 25567 AN: 60264

GnomAD4 genome AF: 0.463 AC: 70144 AN: 151544 Hom.: 16844 Cov.: 0 AF XY: 0.466 AC XY: 34513 AN XY: 74056

African (AFR) AF: 0.582 AC: 24043 AN: 41314

American (AMR) AF: 0.508 AC: 7721 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3466

East Asian (EAS) AF: 0.364 AC: 1866 AN: 5120

South Asian (SAS) AF: 0.477 AC: 2296 AN: 4818

European-Finnish (FIN) AF: 0.422 AC: 4440 AN: 10512

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26749 AN: 67826

Other (OTH) AF: 0.486 AC: 1021 AN: 2100

Alfa AF: 0.427 Hom.: 2968

Asia WGS AF: 0.429 AC: 1495 AN: 3478

EpiCase AF: 0.416

EpiControl AF: 0.422

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Congenital hyperammonemia, type I (5)
-	-	4	not specified (4)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.50
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61509952; hg19: chr2-211421452; COSMIC: COSV51801191; COSMIC: COSV51801191;