rs139579816
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_016203.4(PRKAG2):āc.325T>Gā(p.Ser109Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: š 0.00026 ( 0 hom., cov: 32)
Exomes š: 0.000028 ( 0 hom. )
Consequence
PRKAG2
NM_016203.4 missense
NM_016203.4 missense
Scores
4
16
Clinical Significance
Conservation
PhyloP100: 3.78
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.033177406).
BP6
?
Variant 7-151781293-A-C is Benign according to our data. Variant chr7-151781293-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45715.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr7-151781293-A-C is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000263 (40/152280) while in subpopulation AFR AF= 0.000963 (40/41542). AF 95% confidence interval is 0.000726. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 40 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKAG2 | NM_016203.4 | c.325T>G | p.Ser109Ala | missense_variant | 3/16 | ENST00000287878.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKAG2 | ENST00000287878.9 | c.325T>G | p.Ser109Ala | missense_variant | 3/16 | 1 | NM_016203.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000263 AC: 40AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251200Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135794
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GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461788Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24AN XY: 727188
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GnomAD4 genome ? AF: 0.000263 AC: 40AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 19, 2016 | Variant summary: The PRKAG2 c.325T>G (p.Ser109Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant is located outside the CBS domain region where pathogenic PRKAG2 variants have been known to cluster (InterPro, Oliveira 2003), reducing the likelihood that it is disease causing. This variant was found in 8/120812 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0007761 (8/10308). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic PRKAG2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been found in multiple patients with cardiomyopathy from published (Kindel_2012) as well as unpublished (LMM-PH) sources. The variant did not cosegregate with disease in a family (LMM-PH). Two clinical diagnostic laboratories have classified this variant as uncertain significance. Taken together, this variant is classified as likely benign. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 13, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Ser109Ala var iant in PRKAG2 has been identified in 8/10308 of African chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs139579816). Th is variant has been identified by our laboratory in 3 individuals (1 Black infan t with HCM, 1 Black teenager with RCM/LVNC, and 1 adult of unspecified ethnicity with DCM); however, it was not present in an affected sibling of the infant wit h HCM and was identified in the unaffected mother, both of whom carried another variant of unknown significance in another gene. This variant is located outside the CBS domain region where all pathogenic PRKAG2 variants have been identified to date (Oliveira 2003), reducing the likelihood that it is disease causing. Co mputational prediction tools and conservation analysis also suggest that it may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ser109A la variant is uncertain, these data suggest that it is more likely to be benign. - |
Wolff-Parkinson-White pattern;C1833236:Hypertrophic cardiomyopathy 6;C1849813:Lethal congenital glycogen storage disease of heart Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | PRKAG2 NM_016203.3 exon 3 p.Ser109Ala (c.325T>G): This variant has been reported in the literature in at least one individual with HCM (Kindel 2012 PMID:22555271). This variant is also present in 0.08% (22/24932) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-151478379-A-C) and is present in ClinVar (Variation ID:45715). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 27, 2021 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 11, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Lethal congenital glycogen storage disease of heart Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at