7-151557198-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_016203.4(PRKAG2):​c.*3G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,146 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0089 ( 17 hom., cov: 32)
Exomes 𝑓: 0.00091 ( 23 hom. )

Consequence

PRKAG2
NM_016203.4 3_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.32

Publications

2 publications found
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]
PRKAG2 Gene-Disease associations (from GenCC):
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • hypertrophic cardiomyopathy 6
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
  • PRKAG2-related cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • lethal congenital glycogen storage disease of heart
    Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
  • Wolff-Parkinson-White syndrome
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00893 (1360/152288) while in subpopulation AFR AF = 0.0307 (1277/41558). AF 95% confidence interval is 0.0293. There are 17 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 1360 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRKAG2NM_016203.4 linkc.*3G>A 3_prime_UTR_variant Exon 16 of 16 ENST00000287878.9 NP_057287.2 Q9UGJ0-1A0A090N8Q6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRKAG2ENST00000287878.9 linkc.*3G>A 3_prime_UTR_variant Exon 16 of 16 1 NM_016203.4 ENSP00000287878.3 Q9UGJ0-1

Frequencies

GnomAD3 genomes
AF:
0.00891
AC:
1356
AN:
152170
Hom.:
17
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0307
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00526
GnomAD2 exomes
AF:
0.00233
AC:
583
AN:
249876
AF XY:
0.00169
show subpopulations
Gnomad AFR exome
AF:
0.0323
Gnomad AMR exome
AF:
0.000983
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000981
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.000913
AC:
1334
AN:
1461858
Hom.:
23
Cov.:
31
AF XY:
0.000791
AC XY:
575
AN XY:
727238
show subpopulations
African (AFR)
AF:
0.0322
AC:
1078
AN:
33476
American (AMR)
AF:
0.00127
AC:
57
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.000116
AC:
10
AN:
86256
European-Finnish (FIN)
AF:
0.0000374
AC:
2
AN:
53416
Middle Eastern (MID)
AF:
0.00139
AC:
8
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000468
AC:
52
AN:
1111992
Other (OTH)
AF:
0.00209
AC:
126
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.453
Heterozygous variant carriers
0
69
137
206
274
343
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
40
80
120
160
200
<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:
0.00893
AC:
1360
AN:
152288
Hom.:
17
Cov.:
32
AF XY:
0.00834
AC XY:
621
AN XY:
74468
show subpopulations
African (AFR)
AF:
0.0307
AC:
1277
AN:
41558
American (AMR)
AF:
0.00392
AC:
60
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000162
AC:
11
AN:
68016
Other (OTH)
AF:
0.00520
AC:
11
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
57
114
172
229
286
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.00634
Hom.:
10
Bravo
AF:
0.00998
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 06, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 13, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 23, 2015
Mayo Clinic Laboratories, Mayo Clinic
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:4
Apr 09, 2025
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 13, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

*3G>A in the 3' UTR of PRKAG2: This variant is classified as benign based on its high frequency in the general population (rs113234987; NHLBI Exome Sequencing P roject, http://evs.gs.washington.edu/EVS; MAF >3%). -

Cardiomyopathy Benign:2
Apr 02, 2018
Color Diagnostics, LLC DBA Color Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 24, 2015
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Wolff-Parkinson-White pattern Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hypertrophic cardiomyopathy 6 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1
Dec 08, 2014
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.084
DANN
Benign
0.75
PhyloP100
-1.3
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs113234987; hg19: chr7-151254284; API