rs11552145

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.100

Publications

21 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 -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 VariationId 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 rank	MANE	Protein	UniProt
PCK1	NM_002591.4 link	c.826G>A	p.Glu276Lys	missense_variant	Exon 6 of 10	ENST00000319441.6	NP_002582.3	P35558-1
PCK1	XM_024451888.2 link	c.430G>A	p.Glu144Lys	missense_variant	Exon 5 of 9		XP_024307656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCK1	ENST00000319441.6 link	c.826G>A	p.Glu276Lys	missense_variant	Exon 6 of 10	1	NM_002591.4	ENSP00000319814.4	P35558-1
PCK1	ENST00000467047.1 link	n.2513G>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
PCK1	ENST00000498194.1 link	n.768G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
PCK1	ENST00000470051.1 link	n.*1G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.146

AC:

22132

AN:

152056

Hom.:

2061

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.164

AC:

41015

AN:

250492

AF XY:

0.169

show subpopulations

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 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.:

AF XY:

0.188

AC XY:

136077

AN XY:

725282

show subpopulations

African (AFR)

AF:

0.0378

AC:

1262

AN:

33400

American (AMR)

AF:

0.122

AC:

5426

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

4326

AN:

26092

East Asian (EAS)

AF:

0.00310

AC:

123

AN:

39654

South Asian (SAS)

AF:

0.168

AC:

14437

AN:

86048

European-Finnish (FIN)

AF:

0.223

AC:

11916

AN:

53394

Middle Eastern (MID)

AF:

0.146

AC:

840

AN:

5758

European-Non Finnish (NFE)

AF:

0.202

AC:

223779

AN:

1108308

Other (OTH)

AF:

0.165

AC:

9950

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

10063

20126

30190

40253

50316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7486

14972

22458

29944

37430

<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:

0.146

AC:

22146

AN:

152174

Hom.:

2063

Cov.:

AF XY:

0.146

AC XY:

10834

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0432

AC:

1795

AN:

41522

American (AMR)

AF:

0.132

AC:

2025

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

574

AN:

3472

East Asian (EAS)

AF:

0.00599

AC:

AN:

5178

South Asian (SAS)

AF:

0.151

AC:

728

AN:

4810

European-Finnish (FIN)

AF:

0.219

AC:

2317

AN:

10588

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.208

AC:

14129

AN:

67992

Other (OTH)

AF:

0.136

AC:

288

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

931

1863

2794

3726

4657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.182

Hom.:

9634

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 15, 2021

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Phosphoenolpyruvate carboxykinase deficiency, cytosolic

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.6

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.061

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.23

PhyloP100

0.10

PrimateAI

Benign

0.26

PROVEAN

Benign

0.59

REVEL

Benign

0.030

Sift

Benign

1.0

Sift4G

Benign

0.90

Polyphen

0.0

Vest4

0.077

MPC

0.11

ClinPred

0.000026

GERP RS

-2.2

Varity_R

0.13

gMVP

0.71

Mutation Taster

=90/10

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