chr20-57561480-A-G

Position:

• chr20-57561480-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002591.4(PCK1):​c.69A>G​(p.Leu23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,612,858 control chromosomes in the GnomAD database, including 191,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15133 hom., cov: 33)
  • Exomes 𝑓: 0.49 (176244 hom.)
• Consequence: PCK1 NM_002591.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 20-57561480-A-G is Benign according to our data. Variant chr20-57561480-A-G is described in ClinVar as [Benign]. Clinvar id is 338868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-57561480-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCK1	NM_002591.4	c.69A>G	p.Leu23=	synonymous_variant	2/10	ENST00000319441.6
PCK1	XM_024451888.2	c.-146A>G		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCK1	ENST00000319441.6	c.69A>G	p.Leu23=	synonymous_variant	2/10	1	NM_002591.4	P1
PCK1	ENST00000467047.1	n.401A>G		non_coding_transcript_exon_variant	1/2	1
PCK1	ENST00000475833.1	n.210A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66747 AN: 151936 Hom.: 15144 Cov.: 33

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.464

GnomAD3 exomes AF: 0.450 AC: 112932 AN: 251010 Hom.: 26092 AF XY: 0.457 AC XY: 62059 AN XY: 135680

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.382

Gnomad SAS exome AF: 0.447

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.503

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.487 AC: 712023 AN: 1460804 Hom.: 176244 Cov.: 38 AF XY: 0.487 AC XY: 353808 AN XY: 726732

Gnomad4 AFR exome AF: 0.337

Gnomad4 AMR exome AF: 0.337

Gnomad4 ASJ exome AF: 0.481

Gnomad4 EAS exome AF: 0.350

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.484

GnomAD4 genome AF: 0.439 AC: 66732 AN: 152054 Hom.: 15133 Cov.: 33 AF XY: 0.435 AC XY: 32370 AN XY: 74334

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.478

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.482

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.459

Alfa AF: 0.477 Hom.: 9944

Bravo AF: 0.429

Asia WGS AF: 0.392 AC: 1366 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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	-0.50
CADD	Benign	7.4
DANN	Benign	0.63

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: rs1042521; hg19: chr20-56136536; COSMIC: COSV60126620; COSMIC: COSV60126620;