Genetic Variant NM_002591.4:c.12G>A (chr20-57561423-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002591.4(PCK1):c.12G>A(p.Gln4Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.00124 in 1,612,132 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 13 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 18 hom. )

Consequence

PCK1
NM_002591.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.84

Publications

1 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=-0.67).

BP6

Variant 20-57561423-G-A is Benign according to our data. Variant chr20-57561423-G-A is described in ClinVar as Benign. ClinVar VariationId is 777600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00626 (954/152314) while in subpopulation AFR AF = 0.0216 (897/41566). AF 95% confidence interval is 0.0204. There are 13 homozygotes in GnomAd4. There are 452 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 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.12G>A	p.Gln4Gln	synonymous	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.12G>A	p.Gln4Gln	synonymous	Exon 2 of 10	ENSP00000319814.4	P35558-1
PCK1	ENST00000467047.1	TSL:1	n.344G>A		non_coding_transcript_exon	Exon 1 of 2
PCK1	ENST00000851909.1		c.12G>A	p.Gln4Gln	synonymous	Exon 1 of 9	ENSP00000521968.1

Frequencies

GnomAD3 genomes

AF:

0.00627

AC:

955

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00165

AC:

411

AN:

249684

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000482

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000712

AC:

1039

AN:

1459818

Hom.:

Cov.:

AF XY:

0.000624

AC XY:

453

AN XY:

726060

show subpopulations

African (AFR)

AF:

0.0242

AC:

809

AN:

33454

American (AMR)

AF:

0.000895

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.000116

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.0000572

AC:

AN:

52432

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1111118

Other (OTH)

AF:

0.00156

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00626

AC:

954

AN:

152314

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

452

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0216

AC:

897

AN:

41566

American (AMR)

AF:

0.00255

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00323

Hom.:

Bravo

AF:

0.00705

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Phosphoenolpyruvate carboxykinase deficiency, cytosolic (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.1

(source)

DANN

Benign

0.67

PhyloP100

3.8

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=289/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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