2-210639132-A-T

Variant names:

• chr2-210639132-A-T
• rs116664530
• NM_001875.5:c.2830-18A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001875.5(CPS1):​c.2830-18A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPS1 NM_001875.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001875.5	c.2830-18A>T		intron_variant	Intron 22 of 37	ENST00000233072.10	NP_001866.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000233072.10	c.2830-18A>T		intron_variant	Intron 22 of 37	1	NM_001875.5	ENSP00000233072.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245054 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1444858 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 719390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33014

American (AMR) AF: 0.00 AC: 0 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 85244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098144

Other (OTH) AF: 0.00 AC: 0 AN: 59732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.14
PhyloP100		-0.34

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: rs116664530; hg19: chr2-211503856;