20-57564347-T-C

Variant names:

• chr20-57564347-T-C
• rs2070756
• NM_002591.4:c.1140T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002591.4(PCK1):​c.1140T>C​(p.Gly380Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,613,712 control chromosomes in the GnomAD database, including 455,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48239 hom., cov: 31)
  • Exomes 𝑓: 0.75 (406825 hom.)
• Consequence: PCK1 NM_002591.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.51
• Publications: 23 publications found

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]

PCK1 Gene-Disease associations (from GenCC):

• phosphoenolpyruvate carboxykinase deficiency, cytosolic

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• phosphoenolpyruvate carboxykinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-57564347-T-C is Benign according to our data. Variant chr20-57564347-T-C is described in ClinVar as Benign. ClinVar VariationId is 338889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002591.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	NM_002591.4	MANE Select	c.1140T>C	p.Gly380Gly	synonymous	Exon 7 of 10	NP_002582.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	ENST00000319441.6	TSL:1 MANE Select	c.1140T>C	p.Gly380Gly	synonymous	Exon 7 of 10	ENSP00000319814.4
	PCK1	ENST00000467047.1	TSL:1	n.3268T>C		non_coding_transcript_exon	Exon 1 of 2
	PCK1	ENST00000851909.1		c.1140T>C	p.Gly380Gly	synonymous	Exon 6 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120338 AN: 152002 Hom.: 48186 Cov.: 31

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.751

GnomAD2 exomes AF: 0.748 AC: 188076 AN: 251390 AF XY: 0.742

Gnomad AFR exome AF: 0.928

Gnomad AMR exome AF: 0.730

Gnomad ASJ exome AF: 0.688

Gnomad EAS exome AF: 0.779

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.744

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.745 AC: 1089172 AN: 1461592 Hom.: 406825 Cov.: 51 AF XY: 0.742 AC XY: 539616 AN XY: 727108

African (AFR) AF: 0.928 AC: 31068 AN: 33474

American (AMR) AF: 0.730 AC: 32644 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 17941 AN: 26134

East Asian (EAS) AF: 0.741 AC: 29430 AN: 39700

South Asian (SAS) AF: 0.685 AC: 59045 AN: 86250

European-Finnish (FIN) AF: 0.770 AC: 41156 AN: 53420

Middle Eastern (MID) AF: 0.687 AC: 3962 AN: 5768

European-Non Finnish (NFE) AF: 0.745 AC: 828580 AN: 1111736

Other (OTH) AF: 0.751 AC: 45346 AN: 60392

GnomAD4 genome AF: 0.792 AC: 120452 AN: 152120 Hom.: 48239 Cov.: 31 AF XY: 0.789 AC XY: 58681 AN XY: 74370

African (AFR) AF: 0.925 AC: 38411 AN: 41516

American (AMR) AF: 0.738 AC: 11273 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2390 AN: 3472

East Asian (EAS) AF: 0.775 AC: 3998 AN: 5156

South Asian (SAS) AF: 0.682 AC: 3277 AN: 4808

European-Finnish (FIN) AF: 0.753 AC: 7965 AN: 10576

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.746 AC: 50690 AN: 67986

Other (OTH) AF: 0.754 AC: 1595 AN: 2116

Alfa AF: 0.752 Hom.: 64891

Bravo AF: 0.796

Asia WGS AF: 0.738 AC: 2567 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Phosphoenolpyruvate carboxykinase deficiency, cytosolic (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.11
DANN	Benign	0.34
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070756; hg19: chr20-56139403; COSMIC: COSV60128359; COSMIC: COSV60128359;