rs11552145

chr20-57563592-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002591.4(PCK1):c.826G>A(p.Glu276Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,609,592 control chromosomes in the GnomAD database, including 29,379 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2063 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27316 hom.)
• Consequence: PCK1 NM_002591.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017687678).
• BP6: Variant 20-57563592-G-A is Benign according to our data. Variant chr20-57563592-G-A is described in ClinVar as [Benign]. Clinvar id is 338883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCK1	NM_002591.4	c.826G>A	p.Glu276Lys	missense_variant	6/10	ENST00000319441.6
PCK1	XM_024451888.2	c.430G>A	p.Glu144Lys	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCK1	ENST00000319441.6	c.826G>A	p.Glu276Lys	missense_variant	6/10	1	NM_002591.4	P1
PCK1	ENST00000467047.1	n.2513G>A		non_coding_transcript_exon_variant	1/2	1
PCK1	ENST00000498194.1	n.768G>A		non_coding_transcript_exon_variant	3/3	2
PCK1	ENST00000470051.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22132 AN: 152056 Hom.: 2061 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.00597

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.164 AC: 41015 AN: 250492 Hom.: 3966 AF XY: 0.169 AC XY: 22853 AN XY: 135420

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.00376

Gnomad SAS exome AF: 0.166

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.187 AC: 272059 AN: 1457418 Hom.: 27316 Cov.: 30 AF XY: 0.188 AC XY: 136077 AN XY: 725282

Gnomad4 AFR exome AF: 0.0378

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.00310

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.146 AC: 22146 AN: 152174 Hom.: 2063 Cov.: 32 AF XY: 0.146 AC XY: 10834 AN XY: 74388

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.00599

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.136

Alfa AF: 0.183 Hom.: 4411

Bravo AF: 0.131

TwinsUK AF: 0.196 AC: 725

ALSPAC AF: 0.205 AC: 790

ESP6500AA AF: 0.0520 AC: 229

ESP6500EA AF: 0.195 AC: 1673

ExAC AF: 0.167 AC: 20283

Asia WGS AF: 0.0660 AC: 231 AN: 3478

EpiCase AF: 0.200

EpiControl AF: 0.198

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.6
Dann	Benign	0.54
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.23	N
MutationTaster	Benign	0.99	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.077
MPC		0.11
ClinPred		0.000026	T
GERP RS		-2.2
Varity_R		0.13
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11552145; hg19: chr20-56138648;