Genetic Variant PRKAG3:p.Gly180Gly (chr2-218830071-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

The ENST00000439262.7(PRKAG3):c.540C>T(p.Gly180Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,613,550 control chromosomes in the GnomAD database, including 725 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 0.020 ( 49 hom., cov: 32)

Exomes 𝑓: 0.029 ( 676 hom. )

Consequence

PRKAG3
ENST00000439262.7 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.792

Publications

7 publications found

Variant links:

Genes affected

PRKAG3 (HGNC:9387): (protein kinase AMP-activated non-catalytic subunit gamma 3) The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This subunit is one of the gamma regulatory subunits of AMPK. It is dominantly expressed in skeletal muscle. Studies of the pig counterpart suggest that this subunit may play a key role in the regulation of energy metabolism in skeletal muscle. [provided by RefSeq, Jul 2008]

PRKAG3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP7

Synonymous conserved (PhyloP=-0.792 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0205 (3122/152310) while in subpopulation NFE AF = 0.031 (2111/68032). AF 95% confidence interval is 0.0299. There are 49 homozygotes in GnomAd4. There are 1434 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG3	NM_017431.4 link	c.540C>T	p.Gly180Gly	synonymous_variant	Exon 4 of 14		NP_059127.2	Q9UGI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG3	ENST00000439262.7 link	c.540C>T	p.Gly180Gly	synonymous_variant	Exon 4 of 14	1		ENSP00000397133.3		Q9UGI9-1

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3122

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0338

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0310

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0216

AC:

5416

AN:

250866

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.00542

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0353

Gnomad NFE exome

AF:

0.0311

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0286

AC:

41800

AN:

1461240

Hom.:

676

Cov.:

AF XY:

0.0279

AC XY:

20285

AN XY:

726808

show subpopulations

African (AFR)

AF:

0.00370

AC:

124

AN:

33476

American (AMR)

AF:

0.0135

AC:

603

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0270

AC:

706

AN:

26108

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.00659

AC:

568

AN:

86188

European-Finnish (FIN)

AF:

0.0359

AC:

1915

AN:

53336

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0327

AC:

36329

AN:

1111624

Other (OTH)

AF:

0.0246

AC:

1485

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

2475

4950

7426

9901

12376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1374

2748

4122

5496

6870

<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:

0.0205

AC:

3122

AN:

152310

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1434

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00599

AC:

249

AN:

41562

American (AMR)

AF:

0.0151

AC:

231

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00477

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0338

AC:

359

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0310

AC:

2111

AN:

68032

Other (OTH)

AF:

0.0218

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

164

328

493

657

821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0267

Hom.:

103

Bravo

AF:

0.0189

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0296

EpiControl

AF:

0.0335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.3

(source)

DANN

Benign

0.88

PhyloP100

-0.79

Mutation Taster

=297/3

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

Computational scores

Splicing

Publications

Other links and lift over