20-57564347-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.51

Publications

23 publications found

Variant links:

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

PCK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK1	NM_002591.4 link	c.1140T>C	p.Gly380Gly	synonymous_variant	Exon 7 of 10	ENST00000319441.6	NP_002582.3
PCK1	XM_024451888.2 link	c.744T>C	p.Gly248Gly	synonymous_variant	Exon 6 of 9		XP_024307656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PCK1	ENST00000319441.6 link	c.1140T>C	p.Gly380Gly	synonymous_variant	Exon 7 of 10	1	NM_002591.4	ENSP00000319814.4
PCK1	ENST00000467047.1 link	n.3268T>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
PCK1	ENST00000485958.1 link	n.264T>C		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.792

AC:

120338

AN:

152002

Hom.:

48186

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.742

AC XY:

539616

AN XY:

727108

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

16277

32554

48830

65107

81384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20274

40548

60822

81096

101370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.792

AC:

120452

AN:

152120

Hom.:

48239

Cov.:

AF XY:

0.789

AC XY:

58681

AN XY:

74370

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1260

2519

3779

5038

6298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.752

Hom.:

64891

Bravo

AF:

0.796

Asia WGS

AF:

0.738

AC:

2567

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic

Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.11

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over