rs397517274

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_016203.4(PRKAG2):​c.554A>T​(p.Glu185Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

2
9
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.79
Variant links:
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 Likely_benign. Variant got -5 ACMG points.

BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000263 (4/152202) while in subpopulation AMR AF= 0.000262 (4/15282). AF 95% confidence interval is 0.0000888. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRKAG2NM_016203.4 linkuse as main transcriptc.554A>T p.Glu185Val missense_variant 4/16 ENST00000287878.9 NP_057287.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRKAG2ENST00000287878.9 linkuse as main transcriptc.554A>T p.Glu185Val missense_variant 4/161 NM_016203.4 ENSP00000287878 P3Q9UGJ0-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000437
AC:
11
AN:
251486
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461798
Hom.:
0
Cov.:
30
AF XY:
0.0000193
AC XY:
14
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000291
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000180
Hom.:
0
Bravo
AF:
0.000136
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 16, 2012The Glu185Val variant in PRKAG2 has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein. Additional information is n eeded to fully assess the clinical significance of the Glu185Val variant. -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 28, 2023This missense variant replaces glutamic acid with valine at codon 185 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiovascular disorder (Pottinger et al., 2019, doi: https://doi.org/10.1101/716662) and in an individual affected with sudden unexpected death (PMID: 30878466). This variant has been identified in 11/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 15, 2024Reported in individuals with cardiomyopathy, sudden infant death, and a PRKAG2-related phenotype; however, at least three of these individuals harbored variants in other genes (PMID: 30878466, 32646569, 32009526); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32646569, 32009526, 30878466) -
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024This missense variant replaces glutamic acid with valine at codon 185 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with cardiovascular disorder (Pottinger et al., 2019) and in an individual affected with sudden unexpected death (PMID: 30878466). This variant has been identified in 11/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Lethal congenital glycogen storage disease of heart Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 03, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
CardioboostCm
Benign
0.0023
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.11
T;.;.
Eigen
Benign
-0.0000038
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.56
D;D;D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Benign
1.6
L;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.1
N;N;N
REVEL
Uncertain
0.49
Sift
Uncertain
0.0010
D;D;D
Sift4G
Benign
0.062
T;T;T
Polyphen
0.067
B;.;.
Vest4
0.81
MutPred
0.18
Loss of solvent accessibility (P = 0.0146);.;.;
MVP
0.95
MPC
0.36
ClinPred
0.23
T
GERP RS
5.4
Varity_R
0.17
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs397517274; hg19: chr7-151372636; API