2-210477748-G-A

Variant names:

• chr2-210477748-G-A
• rs111491997
• ENST00000430249.7:c.-16G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001122633.3(CPS1):​c.-34G>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 NM_001122633.3 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]

LANCL1 (HGNC:6508): (LanC like glutathione S-transferase 1) This gene encodes a loosely associated peripheral membrane protein related to the LanC family of bacterial membrane-associated proteins involved in the biosynthesis of antimicrobial peptides. This protein may play a role as a peptide-modifying enzyme component in eukaryotic cells. Previously considered a member of the G-protein-coupled receptor superfamily, this protein is now in the LanC family. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2008]

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPS1	NM_001122633.3	c.-34G>A		5_prime_UTR_variant	Exon 1 of 39		NP_001116105.2
CPS1	NM_001369257.1	c.-154G>A		5_prime_UTR_variant	Exon 1 of 40		NP_001356186.1
LANCL1	XM_005246243.3	c.-279C>T		upstream_gene_variant			XP_005246300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPS1	ENST00000430249.7	c.-16G>A		5_prime_UTR_variant	Exon 1 of 39	1		ENSP00000402608.2
CPS1	ENST00000673510.1	c.-154G>A		5_prime_UTR_variant	Exon 1 of 40			ENSP00000500537.1
CPS1	ENST00000673630.1	c.-268G>A		5_prime_UTR_variant	Exon 1 of 40			ENSP00000501073.1

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

GnomAD2 exomes AF: 0.0152 AC: 3784 AN: 248272 AF XY: 0.0150

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 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

African (AFR) AF: 0.00197 AC: 66 AN: 33478

American (AMR) AF: 0.00674 AC: 301 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0604 AC: 1578 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00177 AC: 152 AN: 86118

European-Finnish (FIN) AF: 0.0383 AC: 2046 AN: 53376

Middle Eastern (MID) AF: 0.0323 AC: 186 AN: 5766

European-Non Finnish (NFE) AF: 0.0134 AC: 14846 AN: 1111424

Other (OTH) AF: 0.0161 AC: 971 AN: 60354

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

African (AFR) AF: 0.00231 AC: 96 AN: 41556

American (AMR) AF: 0.00896 AC: 137 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 208 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.0466 AC: 494 AN: 10602

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1038 AN: 68032

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0160 Hom.: 38

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

Mar 14, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.68
PhyloP100		-0.60
PromoterAI		-0.016	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Publications

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Other links and lift over

dbSNP: rs111491997; hg19: chr2-211342472;