rs147349145
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_016203.4(PRKAG2):c.1267C>A(p.Gln423Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
PRKAG2
NM_016203.4 missense
NM_016203.4 missense
Scores
4
16
Clinical Significance
Conservation
PhyloP100: 5.95
Genes affected
PRKAG2 (HGNC:9386): (protein kinase AMP-activated non-catalytic subunit gamma 2) AMP-activated protein kinase (AMPK) is a heterotrimeric protein composed of a catalytic alpha subunit, a noncatalytic beta subunit, and a noncatalytic regulatory gamma subunit. Various forms of each of these subunits exist, encoded by different genes. AMPK is an important energy-sensing enzyme that monitors cellular energy status and functions by inactivating key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This gene is a member of the AMPK gamma subunit family. Mutations in this gene have been associated with Wolff-Parkinson-White syndrome, familial hypertrophic cardiomyopathy, and glycogen storage disease of the heart. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2015]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.08991507).
BP6
Variant 7-151565852-G-T is Benign according to our data. Variant chr7-151565852-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45693.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000112 (17/152194) while in subpopulation AFR AF= 0.00041 (17/41436). AF 95% confidence interval is 0.000261. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 17 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKAG2 | NM_016203.4 | c.1267C>A | p.Gln423Lys | missense_variant | 12/16 | ENST00000287878.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKAG2 | ENST00000287878.9 | c.1267C>A | p.Gln423Lys | missense_variant | 12/16 | 1 | NM_016203.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152194Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
17
AN:
152194
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251474Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
GnomAD3 exomes
AF:
AC:
6
AN:
251474
Hom.:
AF XY:
AC XY:
2
AN XY:
135908
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461444Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727076
GnomAD4 exome
AF:
AC:
11
AN:
1461444
Hom.:
Cov.:
31
AF XY:
AC XY:
8
AN XY:
727076
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000112 AC: 17AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74352
GnomAD4 genome
AF:
AC:
17
AN:
152194
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
74352
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
0
ExAC
AF:
AC:
4
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiomyopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 20, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 05, 2022 | - - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2008 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2017 | The Q423K variant of uncertain significance in the PRKAG2 gene has not been published as pathogenic nor benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis is inconsistent in its predictions as to whether or not Q423K is damaging to the protein structure/function. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved in mammals; however, K423 is tolerated in at least two non-mammalian species. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with PRKAG2-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 27, 2014 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2021 | The c.1267C>A (p.Q423K) alteration is located in exon 12 (coding exon 12) of the PRKAG2 gene. This alteration results from a C to A substitution at nucleotide position 1267, causing the glutamine (Q) at amino acid position 423 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Lethal congenital glycogen storage disease of heart Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at