rs28359554

chr20-57566235-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002591.4(PCK1):c.*431T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 159,590 control chromosomes in the GnomAD database, including 973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.088 (945 hom., cov: 32)
  • Exomes 𝑓: 0.047 (28 hom.)
• Consequence: PCK1 NM_002591.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.439

Genes affected

PCK1 (HGNC:8724): (phosphoenolpyruvate carboxykinase 1) This gene is a main control point for the regulation of gluconeogenesis. The cytosolic enzyme encoded by this gene, along with GTP, catalyzes the formation of phosphoenolpyruvate from oxaloacetate, with the release of carbon dioxide and GDP. The expression of this gene can be regulated by insulin, glucocorticoids, glucagon, cAMP, and diet. Defects in this gene are a cause of cytosolic phosphoenolpyruvate carboxykinase deficiency. A mitochondrial isozyme of the encoded protein also has been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-57566235-T-C is Benign according to our data. Variant chr20-57566235-T-C is described in ClinVar as [Benign]. Clinvar id is 338916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCK1	NM_002591.4	c.*431T>C		3_prime_UTR_variant	10/10	ENST00000319441.6
PCK1	XM_024451888.2	c.*431T>C		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCK1	ENST00000319441.6	c.*431T>C		3_prime_UTR_variant	10/10	1	NM_002591.4	P1
PCK1	ENST00000467047.1	n.4942T>C		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0881 AC: 13371 AN: 151768 Hom.: 941 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0987

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.0826

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.0472 AC: 364 AN: 7704 Hom.: 28 Cov.: 0 AF XY: 0.0481 AC XY: 195 AN XY: 4056

Gnomad4 AFR exome AF: 0.00521

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.0758

Gnomad4 SAS exome AF: 0.0272

Gnomad4 FIN exome AF: 0.0589

Gnomad4 NFE exome AF: 0.0379

Gnomad4 OTH exome AF: 0.0510

GnomAD4 genome AF: 0.0882 AC: 13389 AN: 151886 Hom.: 945 Cov.: 32 AF XY: 0.0936 AC XY: 6945 AN XY: 74226

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0987

Gnomad4 NFE AF: 0.0826

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0913 Hom.: 606

Bravo AF: 0.0946

Asia WGS AF: 0.190 AC: 658 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.30
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs28359554; hg19: chr20-56141291;