rs28359554

Variant names:

Variant summary

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

The ENST00000467047.1(PCK1):n.4942T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 159,590 control chromosomes in the GnomAD database, including 973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.088 ( 945 hom., cov: 32)

Exomes 𝑓: 0.047 ( 28 hom. )

Consequence

PCK1
ENST00000467047.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.439

Publications

4 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 (BayesDel_noAF=-0.85).

BP6

Variant 20-57566235-T-C is Benign according to our data. Variant chr20-57566235-T-C is described in ClinVar as Benign. ClinVar VariationId is 338916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000467047.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	NM_002591.4	MANE Select	c.*431T>C		3_prime_UTR	Exon 10 of 10	NP_002582.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCK1	ENST00000467047.1	TSL:1	n.4942T>C		non_coding_transcript_exon	Exon 2 of 2
	PCK1	ENST00000319441.6	TSL:1 MANE Select	c.*431T>C		3_prime_UTR	Exon 10 of 10	ENSP00000319814.4

Frequencies

GnomAD3 genomes

AF:

0.0881

AC:

13371

AN:

151768

Hom.:

941

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0198

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.143

Gnomad EAS

AF:

0.263

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.0987

Gnomad MID

AF:

0.179

Gnomad NFE

AF:

0.0826

Gnomad OTH

AF:

0.102

GnomAD4 exome

AF:

0.0472

AC:

364

AN:

7704

Hom.:

Cov.:

AF XY:

0.0481

AC XY:

195

AN XY:

4056

show subpopulations

African (AFR)

AF:

0.00521

AC:

AN:

192

American (AMR)

AF:

0.111

AC:

AN:

750

Ashkenazi Jewish (ASJ)

AF:

0.0588

AC:

AN:

170

East Asian (EAS)

AF:

0.0758

AC:

AN:

198

South Asian (SAS)

AF:

0.0272

AC:

AN:

368

European-Finnish (FIN)

AF:

0.0589

AC:

AN:

526

Middle Eastern (MID)

AF:

0.0417

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0379

AC:

192

AN:

5064

Other (OTH)

AF:

0.0510

AC:

AN:

412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0882

AC:

13389

AN:

151886

Hom.:

945

Cov.:

AF XY:

0.0936

AC XY:

6945

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.0197

AC:

816

AN:

41456

American (AMR)

AF:

0.212

AC:

3221

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

497

AN:

3468

East Asian (EAS)

AF:

0.263

AC:

1354

AN:

5144

South Asian (SAS)

AF:

0.107

AC:

516

AN:

4812

European-Finnish (FIN)

AF:

0.0987

AC:

1038

AN:

10516

Middle Eastern (MID)

AF:

0.178

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0826

AC:

5614

AN:

67958

Other (OTH)

AF:

0.107

AC:

226

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

517

1033

1550

2066

2583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0904

Hom.:

680

Bravo

AF:

0.0946

Asia WGS

AF:

0.190

AC:

658

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.30

(source)

DANN

Benign

0.68

PhyloP100

-0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over