chr2-210477748-G-A

Position:

• chr2-210477748-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000430249.7(CPS1):​c.-16G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,276 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (31 hom., cov: 32)
  • Exomes 𝑓: 0.014 (241 hom.)
• Consequence: CPS1 ENST00000430249.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.601

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: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-210477748-G-A is Benign according to our data. Variant chr2-210477748-G-A is described in ClinVar as [Benign]. Clinvar id is 380167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-210477748-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0133 (2023/152270) while in subpopulation NFE AF= 0.0153 (1038/68032). AF 95% confidence interval is 0.0145. There are 31 homozygotes in gnomad4. There are 1119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPS1	NM_001122633.3	c.-34G>A		5_prime_UTR_variant	1/39		NP_001116105.2
CPS1	NM_001369257.1	c.-154G>A		5_prime_UTR_variant	1/40		NP_001356186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000430249.7	c.-16G>A		5_prime_UTR_variant	1/39	1		ENSP00000402608
CPS1	ENST00000673510.1	c.-154G>A		5_prime_UTR_variant	1/40			ENSP00000500537	P1
CPS1	ENST00000673630.1	c.-268G>A		5_prime_UTR_variant	1/40			ENSP00000501073	P1
CPS1	ENST00000673711.1	c.-34G>A		5_prime_UTR_variant	1/39			ENSP00000501022	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2023 AN: 152152 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.0600

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0152 AC: 3784 AN: 248272 Hom.: 75 AF XY: 0.0150 AC XY: 2025 AN XY: 134912

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.0598

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.0424

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0138 AC: 20148 AN: 1461006 Hom.: 241 Cov.: 29 AF XY: 0.0136 AC XY: 9920 AN XY: 726744

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00674

Gnomad4 ASJ exome AF: 0.0604

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.0383

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0133 AC: 2023 AN: 152270 Hom.: 31 Cov.: 32 AF XY: 0.0150 AC XY: 1119 AN XY: 74450

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00896

Gnomad4 ASJ AF: 0.0600

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0466

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0194 Hom.: 10

Bravo AF: 0.0100

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111491997; hg19: chr2-211342472;