rs66628686

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016203.4(PRKAG2):c.-26C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,598,058 control chromosomes in the GnomAD database, including 18,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1807 hom., cov: 32)

Exomes 𝑓: 0.14 ( 16659 hom. )

Consequence

PRKAG2
NM_016203.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.52

Publications

9 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 links:

PRKAG2-AS1 (HGNC:40468): (PRKAG2 antisense RNA 1)

PRKAG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 7-151876646-G-A is Benign according to our data. Variant chr7-151876646-G-A is described in ClinVar as Benign. ClinVar VariationId is 260692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4 link	c.-26C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	ENST00000287878.9	NP_057287.2	Q9UGJ0-1A0A090N8Q6
PRKAG2	NM_016203.4 link	c.-26C>T		5_prime_UTR_variant	Exon 1 of 16	ENST00000287878.9	NP_057287.2	Q9UGJ0-1A0A090N8Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9 link	c.-26C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	1	NM_016203.4	ENSP00000287878.3		Q9UGJ0-1
PRKAG2	ENST00000287878.9 link	c.-26C>T		5_prime_UTR_variant	Exon 1 of 16	1	NM_016203.4	ENSP00000287878.3		Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22415

AN:

152038

Hom.:

1810

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.217

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.240

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.137

GnomAD2 exomes

AF:

0.176

AC:

42586

AN:

242650

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.142

Gnomad AMR exome

AF:

0.308

Gnomad ASJ exome

AF:

0.134

Gnomad EAS exome

AF:

0.248

Gnomad FIN exome

AF:

0.164

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.151

GnomAD4 exome

AF:

0.144

AC:

207749

AN:

1445902

Hom.:

16659

Cov.:

AF XY:

0.144

AC XY:

104027

AN XY:

720176

show subpopulations

African (AFR)

AF:

0.142

AC:

4718

AN:

33324

American (AMR)

AF:

0.298

AC:

13313

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

3482

AN:

26100

East Asian (EAS)

AF:

0.247

AC:

9805

AN:

39636

South Asian (SAS)

AF:

0.212

AC:

18275

AN:

86148

European-Finnish (FIN)

AF:

0.165

AC:

7363

AN:

44596

Middle Eastern (MID)

AF:

0.0479

AC:

276

AN:

5756

European-Non Finnish (NFE)

AF:

0.128

AC:

141763

AN:

1105606

Other (OTH)

AF:

0.146

AC:

8754

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

9094

18188

27283

36377

45471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5438

10876

16314

21752

27190

<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:

0.147

AC:

22415

AN:

152156

Hom.:

1807

Cov.:

AF XY:

0.150

AC XY:

11164

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.136

AC:

5648

AN:

41508

American (AMR)

AF:

0.217

AC:

3321

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

449

AN:

3470

East Asian (EAS)

AF:

0.240

AC:

1241

AN:

5170

South Asian (SAS)

AF:

0.224

AC:

1080

AN:

4818

European-Finnish (FIN)

AF:

0.161

AC:

1704

AN:

10596

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.125

AC:

8521

AN:

67992

Other (OTH)

AF:

0.137

AC:

289

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

975

1950

2925

3900

4875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.143

Hom.:

986

Bravo

AF:

0.153

Asia WGS

AF:

0.247

AC:

857

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16115789, 21813245, 20022652) -

Wolff-Parkinson-White pattern

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypertrophic cardiomyopathy 6

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lethal congenital glycogen storage disease of heart

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

1.5

PromoterAI

-0.061

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over