chr20-57561475-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002591.4(PCK1):ā€‹c.64A>Gā€‹(p.Ser22Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,613,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00043 ( 1 hom., cov: 33)
Exomes š‘“: 0.00050 ( 0 hom. )

Consequence

PCK1
NM_002591.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.443
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.043637663).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PCK1NM_002591.4 linkuse as main transcriptc.64A>G p.Ser22Gly missense_variant 2/10 ENST00000319441.6
PCK1XM_024451888.2 linkuse as main transcriptc.-151A>G 5_prime_UTR_variant 2/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCK1ENST00000319441.6 linkuse as main transcriptc.64A>G p.Ser22Gly missense_variant 2/101 NM_002591.4 P1P35558-1
PCK1ENST00000467047.1 linkuse as main transcriptn.396A>G non_coding_transcript_exon_variant 1/21
PCK1ENST00000475833.1 linkuse as main transcriptn.205A>G non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.000434
AC:
66
AN:
152226
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000723
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000620
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000852
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000247
AC:
62
AN:
251178
Hom.:
0
AF XY:
0.000236
AC XY:
32
AN XY:
135756
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.000186
Gnomad NFE exome
AF:
0.000440
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000496
AC:
725
AN:
1461532
Hom.:
0
Cov.:
30
AF XY:
0.000486
AC XY:
353
AN XY:
727050
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.0000940
Gnomad4 NFE exome
AF:
0.000594
Gnomad4 OTH exome
AF:
0.000729
GnomAD4 genome
AF:
0.000433
AC:
66
AN:
152344
Hom.:
1
Cov.:
33
AF XY:
0.000349
AC XY:
26
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.0000721
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000853
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000519
Hom.:
0
Bravo
AF:
0.000431
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000930
AC:
8
ExAC
AF:
0.000189
AC:
23
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000600
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Phosphoenolpyruvate carboxykinase deficiency, cytosolic Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 06, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 04, 2023The c.64A>G (p.S22G) alteration is located in exon 2 (coding exon 1) of the PCK1 gene. This alteration results from a A to G substitution at nucleotide position 64, causing the serine (S) at amino acid position 22 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 20, 2022This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 22 of the PCK1 protein (p.Ser22Gly). This variant is present in population databases (rs140235265, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PCK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 896030). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.26
T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.47
N
LIST_S2
Benign
0.58
T
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.044
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
0.95
D;D
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.035
Sift
Benign
0.080
T
Sift4G
Benign
0.33
T
Polyphen
0.0
B
Vest4
0.11
MVP
0.37
MPC
0.086
ClinPred
0.023
T
GERP RS
2.0
Varity_R
0.088
gMVP
0.49

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.

Other links and lift over

dbSNP: rs140235265; hg19: chr20-56136531; API