Genetic Variant PRKAG2:p.Pro69Pro (chr7-151781411-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_016203.4(PRKAG2):c.207G>A(p.Pro69Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,609,018 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0056 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 100 hom. )

Consequence

PRKAG2
NM_016203.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -4.85

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 7-151781411-C-T is Benign according to our data. Variant chr7-151781411-C-T is described in ClinVar as Benign. ClinVar VariationId is 45709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.85 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00565 (860/152214) while in subpopulation AMR AF = 0.0419 (641/15294). AF 95% confidence interval is 0.0392. There are 24 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 860 AD gene.

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.207G>A	p.Pro69Pro	synonymous	Exon 3 of 16	NP_057287.2
PRKAG2	NM_001407021.1		c.207G>A	p.Pro69Pro	synonymous	Exon 3 of 15	NP_001393950.1
PRKAG2	NM_001407022.1		c.207G>A	p.Pro69Pro	synonymous	Exon 3 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.207G>A	p.Pro69Pro	synonymous	Exon 3 of 16	ENSP00000287878.3	Q9UGJ0-1
PRKAG2	ENST00000392801.6	TSL:1	c.75G>A	p.Pro25Pro	synonymous	Exon 3 of 16	ENSP00000376549.2	Q9UGJ0-3
PRKAG2	ENST00000488258.5	TSL:1	n.207G>A		non_coding_transcript_exon	Exon 3 of 10	ENSP00000420783.1	F8WDA1

Frequencies

GnomAD3 genomes

AF:

0.00565

AC:

860

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0420

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0270

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00938

AC:

2210

AN:

235578

AF XY:

0.00751

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.0472

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0304

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000767

Gnomad OTH exome

AF:

0.00966

GnomAD4 exome

AF:

0.00270

AC:

3939

AN:

1456804

Hom.:

100

Cov.:

AF XY:

0.00244

AC XY:

1766

AN XY:

724432

show subpopulations

African (AFR)

AF:

0.000419

AC:

AN:

33430

American (AMR)

AF:

0.0448

AC:

1969

AN:

43988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.0421

AC:

1662

AN:

39512

South Asian (SAS)

AF:

0.000559

AC:

AN:

85824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52318

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.000102

AC:

113

AN:

1110128

Other (OTH)

AF:

0.00220

AC:

132

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

246

491

737

982

1228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00565

AC:

860

AN:

152214

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

521

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41528

American (AMR)

AF:

0.0419

AC:

641

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0270

AC:

140

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68008

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00138

Hom.:

Bravo

AF:

0.00782

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Cardiomyopathy (2)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

Hypertrophic cardiomyopathy 6 (1)

Lethal congenital glycogen storage disease of heart (1)

Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.3

(source)

DANN

Benign

0.70

PhyloP100

-4.8

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over