rs707555

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002591.4(PCK1):c.550G>C(p.Val184Leu) variant causes a missense change. The variant allele was found at a frequency of 0.856 in 1,613,292 control chromosomes in the GnomAD database, including 593,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 59909 hom., cov: 35)

Exomes 𝑓: 0.85 ( 533423 hom. )

Consequence

PCK1
NM_002591.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.0281385E-7).

BP6

Variant 20-57562839-G-C is Benign according to our data. Variant chr20-57562839-G-C is described in ClinVar as [Benign]. Clinvar id is 338879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-57562839-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCK1	NM_002591.4 linkuse as main transcript	c.550G>C	p.Val184Leu	missense_variant	4/10	ENST00000319441.6	NP_002582.3
PCK1	XM_024451888.2 linkuse as main transcript	c.154G>C	p.Val52Leu	missense_variant	3/9		XP_024307656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCK1	ENST00000319441.6 linkuse as main transcript	c.550G>C	p.Val184Leu	missense_variant	4/10	1	NM_002591.4	ENSP00000319814	P1	P35558-1
PCK1	ENST00000467047.1 linkuse as main transcript	n.1760G>C		non_coding_transcript_exon_variant	1/2	1
PCK1	ENST00000470051.1 linkuse as main transcript	n.6G>C		non_coding_transcript_exon_variant	1/2	2
PCK1	ENST00000498194.1 linkuse as main transcript	n.492G>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.884

AC:

134596

AN:

152200

Hom.:

59857

Cov.:

show subpopulations

Gnomad AFR

AF:

0.973

Gnomad AMI

AF:

0.928

Gnomad AMR

AF:

0.837

Gnomad ASJ

AF:

0.837

Gnomad EAS

AF:

0.783

Gnomad SAS

AF:

0.742

Gnomad FIN

AF:

0.860

Gnomad MID

AF:

0.918

Gnomad NFE

AF:

0.864

Gnomad OTH

AF:

0.880

GnomAD3 exomes

AF:

0.841

AC:

211380

AN:

251210

Hom.:

89379

AF XY:

0.837

AC XY:

113623

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.975

Gnomad AMR exome

AF:

0.797

Gnomad ASJ exome

AF:

0.834

Gnomad EAS exome

AF:

0.785

Gnomad SAS exome

AF:

0.744

Gnomad FIN exome

AF:

0.867

Gnomad NFE exome

AF:

0.866

Gnomad OTH exome

AF:

0.853

GnomAD4 exome

AF:

0.853

AC:

1246922

AN:

1460974

Hom.:

533423

Cov.:

AF XY:

0.850

AC XY:

618007

AN XY:

726796

show subpopulations

Gnomad4 AFR exome

AF:

0.977

Gnomad4 AMR exome

AF:

0.798

Gnomad4 ASJ exome

AF:

0.837

Gnomad4 EAS exome

AF:

0.749

Gnomad4 SAS exome

AF:

0.747

Gnomad4 FIN exome

AF:

0.872

Gnomad4 NFE exome

AF:

0.863

Gnomad4 OTH exome

AF:

0.856

GnomAD4 genome

AF:

0.884

AC:

134704

AN:

152318

Hom.:

59909

Cov.:

AF XY:

0.879

AC XY:

65481

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.973

Gnomad4 AMR

AF:

0.836

Gnomad4 ASJ

AF:

0.837

Gnomad4 EAS

AF:

0.784

Gnomad4 SAS

AF:

0.742

Gnomad4 FIN

AF:

0.860

Gnomad4 NFE

AF:

0.864

Gnomad4 OTH

AF:

0.882

Alfa

AF:

0.859

Hom.:

38121

Bravo

AF:

0.887

TwinsUK

AF:

0.861

AC:

3194

ALSPAC

AF:

0.860

AC:

3314

ESP6500AA

AF:

0.970

AC:

4276

ESP6500EA

AF:

0.866

AC:

7445

ExAC

AF:

0.846

AC:

102732

Asia WGS

AF:

0.774

AC:

2692

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	This variant is associated with the following publications: (PMID: 19070910) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.23

DEOGEN2

Benign

0.057

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.69

MetaRNN

Benign

7.0e-7

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-3.7

MutationTaster

Benign

0.99

P;P;P

PrimateAI

Uncertain

0.53

PROVEAN

Benign

1.8

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.13

MutPred

0.20

Gain of helix (P = 0.132);

MPC

0.092

ClinPred

0.0053

GERP RS

5.1

Varity_R

0.12

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over