rs147120329

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002591.4(PCK1):c.7C>T(p.Pro3Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,610,994 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

PCK1
NM_002591.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.65

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007808417).

BP6

Variant 20-57561418-C-T is Benign according to our data. Variant chr20-57561418-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 788182.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

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.7C>T	p.Pro3Ser	missense	Exon 2 of 10	NP_002582.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCK1	ENST00000319441.6	TSL:1 MANE Select	c.7C>T	p.Pro3Ser	missense	Exon 2 of 10	ENSP00000319814.4	P35558-1
PCK1	ENST00000467047.1	TSL:1	n.339C>T		non_coding_transcript_exon	Exon 1 of 2
PCK1	ENST00000851909.1		c.7C>T	p.Pro3Ser	missense	Exon 1 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00170

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00132

AC:

330

AN:

249344

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000876

Gnomad NFE exome

AF:

0.00266

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.00182

AC:

2657

AN:

1458680

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1300

AN XY:

725466

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33424

American (AMR)

AF:

0.0000447

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86154

European-Finnish (FIN)

AF:

0.00117

AC:

AN:

52298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00228

AC:

2527

AN:

1110274

Other (OTH)

AF:

0.000995

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

112

224

335

447

559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.000886

AC:

135

AN:

152314

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41570

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00171

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00171

AC:

208

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00219

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Phosphoenolpyruvate carboxykinase deficiency, cytosolic (2)

Inborn genetic diseases (1)

PCK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.096

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.60

M_CAP

Benign

0.015

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

PhyloP100

3.7

PrimateAI

Benign

0.42

PROVEAN

Benign

0.11

REVEL

Benign

0.12

Sift

Benign

0.075

Sift4G

Benign

0.10

Polyphen

0.0080

Vest4

0.26

MVP

0.42

MPC

0.095

ClinPred

0.017

GERP RS

5.7

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.069

gMVP

0.74

Mutation Taster

=167/133

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over