rs6070157

Positions:

• chr20-57562128-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002591.4(PCK1):​c.282C>T​(p.Ile94=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,658 control chromosomes in the GnomAD database, including 30,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2424 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28131 hom.)
• Consequence: PCK1 NM_002591.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.472

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 20-57562128-C-T is Benign according to our data. Variant chr20-57562128-C-T is described in ClinVar as [Benign]. Clinvar id is 338874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.472 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCK1	NM_002591.4	c.282C>T	p.Ile94=	synonymous_variant	3/10	ENST00000319441.6
PCK1	XM_024451888.2	c.10+493C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCK1	ENST00000319441.6	c.282C>T	p.Ile94=	synonymous_variant	3/10	1	NM_002591.4	P1
PCK1	ENST00000467047.1	n.1049C>T		non_coding_transcript_exon_variant	1/2	1
PCK1	ENST00000475833.1	n.858C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26059 AN: 152038 Hom.: 2416 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.172 AC: 43260 AN: 251326 Hom.: 4213 AF XY: 0.176 AC XY: 23846 AN XY: 135858

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.00794

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.191 AC: 279285 AN: 1461502 Hom.: 28131 Cov.: 33 AF XY: 0.192 AC XY: 139361 AN XY: 727064

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.00509

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.204

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.172 AC: 26099 AN: 152156 Hom.: 2424 Cov.: 33 AF XY: 0.170 AC XY: 12649 AN XY: 74386

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.156

Alfa AF: 0.195 Hom.: 6685

Bravo AF: 0.160

Asia WGS AF: 0.0800 AC: 281 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.199

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.41
CADD	Benign	15
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6070157; hg19: chr20-56137184;