rs8192708

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.799A>G(p.Ile267Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,592,498 control chromosomes in the GnomAD database, including 9,714 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 756 hom., cov: 32)

Exomes 𝑓: 0.11 ( 8958 hom. )

Consequence

PCK1
NM_002591.4 missense, splice_region

Scores

Splicing: ADA: 0.1511

Clinical Significance

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

Conservation

PhyloP100: 8.82

Publications

33 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=0.003664881).

BP6

Variant 20-57563565-A-G is Benign according to our data. Variant chr20-57563565-A-G is described in ClinVar as Benign. ClinVar VariationId is 338882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCK1	NM_002591.4 link	c.799A>G	p.Ile267Val	missense_variant, splice_region_variant	Exon 6 of 10	ENST00000319441.6	NP_002582.3	P35558-1
PCK1	XM_024451888.2 link	c.403A>G	p.Ile135Val	missense_variant, splice_region_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.799A>G	p.Ile267Val	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_002591.4	ENSP00000319814.4	P35558-1
PCK1	ENST00000467047.1 link	n.2486A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
PCK1	ENST00000470051.1 link	n.383A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 2	2
PCK1	ENST00000498194.1 link	n.741A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0923

AC:

14030

AN:

152048

Hom.:

757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0482

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.0996

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0605

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.0927

AC:

22581

AN:

243570

AF XY:

0.0947

show subpopulations

Gnomad AFR exome

AF:

0.0479

Gnomad AMR exome

AF:

0.0670

Gnomad ASJ exome

AF:

0.149

Gnomad EAS exome

AF:

0.000893

Gnomad FIN exome

AF:

0.0976

Gnomad NFE exome

AF:

0.123

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.107

AC:

153945

AN:

1440332

Hom.:

8958

Cov.:

AF XY:

0.107

AC XY:

76581

AN XY:

716458

show subpopulations

African (AFR)

AF:

0.0489

AC:

1601

AN:

32720

American (AMR)

AF:

0.0688

AC:

2932

AN:

42626

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

3940

AN:

25698

East Asian (EAS)

AF:

0.000532

AC:

AN:

39474

South Asian (SAS)

AF:

0.0625

AC:

5274

AN:

84414

European-Finnish (FIN)

AF:

0.0947

AC:

5050

AN:

53300

Middle Eastern (MID)

AF:

0.195

AC:

1110

AN:

5692

European-Non Finnish (NFE)

AF:

0.117

AC:

127820

AN:

1096902

Other (OTH)

AF:

0.104

AC:

6197

AN:

59506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

6056

12111

18167

24222

30278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4428

8856

13284

17712

22140

<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:

0.0922

AC:

14024

AN:

152166

Hom.:

756

Cov.:

AF XY:

0.0899

AC XY:

6684

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0480

AC:

1995

AN:

41522

American (AMR)

AF:

0.0995

AC:

1520

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

526

AN:

3472

East Asian (EAS)

AF:

0.000773

AC:

AN:

5174

South Asian (SAS)

AF:

0.0604

AC:

291

AN:

4820

European-Finnish (FIN)

AF:

0.102

AC:

1083

AN:

10580

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8073

AN:

68004

Other (OTH)

AF:

0.128

AC:

270

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

658

1316

1975

2633

3291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.110

Hom.:

3751

Bravo

AF:

0.0908

TwinsUK

AF:

0.132

AC:

488

ALSPAC

AF:

0.126

AC:

484

ESP6500AA

AF:

0.0443

AC:

195

ESP6500EA

AF:

0.127

AC:

1089

ExAC

AF:

0.0908

AC:

11019

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.134

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20574532, 21152065) -

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

Mar 06, 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

0.26

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

PhyloP100

8.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.69

REVEL

Benign

0.22

Sift

Benign

0.052

Sift4G

Uncertain

0.050

Polyphen

0.99

Vest4

0.29

MPC

0.46

ClinPred

0.038

GERP RS

5.4

Varity_R

0.24

gMVP

0.71

Mutation Taster

=31/69

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.15

dbscSNV1_RF

Benign

0.20

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

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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