Genetic Variant PRKAG2:p.Arg302Gln (chr7-151576412-C-T) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM2PM5PP3_StrongPP5_Very_Strong

The NM_016203.4(PRKAG2):c.905G>A(p.Arg302Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002059124: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:14722619, 15611370, 20031621, 23992123)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 7.70

Publications

89 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 6
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, 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: Genomics England PanelApp
Wolff-Parkinson-White syndrome
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

PRKAG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002059124: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 14722619, 15611370, 20031621, 23992123).; SCV000803584: PS3 upgraded in strength to Very Strong (PMID:14722619,11827995,15611370,28917552).; SCV002557884: "Functional studies have shown that AMPK enzymatic activity is significantly reduced by this variant and transgenic mouse models carrying this variant recapitulate the human phenotype." PMID:23778007, 15611370; SCV000208946: Functional studies have demonstrated that transgenic animal models harboring p.(R302Q) develop a phenotype congruent to the human disease spectrum, including reduced cardiac function, LVH, prolonged QRS, ventricular pre-excitation, increased cardiac glycogen stores, and/or reduced AMPK activity (Sidhu et al., 2005; Folmes et al., 2009; Thorn et al., 2013; Zhang et al., 2014); SCV000924905: "Folmes K et al., 2009: expression of R302Q PRKAG2 in transgenic mice was shown to alter protein function and leading to increased glycogen content of the heart tissue, explaining the glycogen storage cardiomyopathy caused by PRKAG2 mutations" Folmes K et al., 2009; SCV000551577: Experimental studies have shown that this missense change affects PRKAG2 function (PMID: 14722619, 15611370, 20031621, 23992123).; SCV000739914: "In vitro functional studies and in vivo studies of transgenic mice have demonstrated abnormal protein function and increased cardiac glycogen storage as a result of this mutation (Scott et al. J Clin Invest. 2004 Jan;113:274-84; Sidhu et al. Circulation. 2005 Jan;111:21-9; Folmes et al. Circ Cardiovasc Genet. 2009 Oct;2:457-66; Zhang et al. J Cardiol. 2013 Oct;62:241-8; Thorn et al. EJNMMI Res. 2013;3:48)."; SCV000062638: "In vitro and in vivo functional studies, including animal models in mouse, have demonstrated that this variant impacts protein function and causes disease that is similar to what has been observed in humans." PMID:23829931; PMID:23778007; PMID:27133129; PMID:29452156; SCV006064428: An in vitro functional study has shown that this variant causes normal intracellular localization but significantly reduced protein expression levels (PMID: 23778007).; SCV002500393: The most pronounced variant effect results in impaired binding of AMP to PRKAG2 protein. Scott_2004

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-151576412-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 533881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 7-151576412-C-T is Pathogenic according to our data. Variant chr7-151576412-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016203.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRKAG2	NM_016203.4	MANE Select	c.905G>A	p.Arg302Gln	missense	Exon 7 of 16	NP_057287.2
PRKAG2	NM_001407021.1		c.905G>A	p.Arg302Gln	missense	Exon 7 of 15	NP_001393950.1
PRKAG2	NM_001407022.1		c.902G>A	p.Arg301Gln	missense	Exon 7 of 15	NP_001393951.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.905G>A	p.Arg302Gln	missense	Exon 7 of 16	ENSP00000287878.3	Q9UGJ0-1
PRKAG2	ENST00000392801.6	TSL:1	c.773G>A	p.Arg258Gln	missense	Exon 7 of 16	ENSP00000376549.2	Q9UGJ0-3
PRKAG2	ENST00000418337.6	TSL:1	c.182G>A	p.Arg61Gln	missense	Exon 3 of 12	ENSP00000387386.2	Q9UGJ0-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459242

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109692

Other (OTH)

AF:

0.00

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000100

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Hypertrophic cardiomyopathy 6 (4)

Wolff-Parkinson-White pattern (3)

Cardiomyopathy (2)

Hypertrophic cardiomyopathy (2)

Cardiovascular phenotype (1)

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)

Lethal congenital glycogen storage disease of heart (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.5

PhyloP100

7.7

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.84

Sift

Uncertain

0.021

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.95

MutPred

0.90

Loss of sheet (P = 0.1158)

MVP

0.99

MPC

1.5

ClinPred

0.99

GERP RS

4.5

Varity_R

0.51

gMVP

0.81

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over