dbSNP rs33985460: PRKAG3:p.Arg340Trp (chr2-218827078-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_017431.4(PRKAG3):c.1018C>T(p.Arg340Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0522 in 1,613,264 control chromosomes in the GnomAD database, including 2,583 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.038 ( 147 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2436 hom. )

Consequence

PRKAG3
NM_017431.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.91

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076971054).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG3	NM_017431.4 link	c.1018C>T	p.Arg340Trp	missense_variant	Exon 10 of 14		NP_059127.2	Q9UGI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
PRKAG3	ENST00000439262.7 link	c.1018C>T	p.Arg340Trp	missense_variant	Exon 10 of 14	1	ENSP00000397133.3	Q9UGI9-1
PRKAG3	ENST00000529249.5 link	c.1018C>T	p.Arg340Trp	missense_variant	Exon 10 of 13	1	ENSP00000436068.1	Q9UGI9-1
PRKAG3	ENST00000470307.6 link	n.972C>T		non_coding_transcript_exon_variant	Exon 9 of 11	5	ENSP00000419272.2	B4DUK8
PRKAG3	ENST00000490971.1 link	n.1176C>T		non_coding_transcript_exon_variant	Exon 9 of 9	2

Frequencies

GnomAD3 genomes

AF:

0.0377

AC:

5741

AN:

152192

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00994

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0421

Gnomad ASJ

AF:

0.0346

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0697

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.0955

Gnomad NFE

AF:

0.0565

Gnomad OTH

AF:

0.0449

GnomAD3 exomes

AF:

0.0472

AC:

11858

AN:

251442

Hom.:

342

AF XY:

0.0500

AC XY:

6800

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00917

Gnomad AMR exome

AF:

0.0487

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0759

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0566

Gnomad OTH exome

AF:

0.0515

GnomAD4 exome

AF:

0.0537

AC:

78454

AN:

1460954

Hom.:

2436

Cov.:

AF XY:

0.0548

AC XY:

39856

AN XY:

726794

show subpopulations

Gnomad4 AFR exome

AF:

0.00974

Gnomad4 AMR exome

AF:

0.0483

Gnomad4 ASJ exome

AF:

0.0381

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0780

Gnomad4 FIN exome

AF:

0.0250

Gnomad4 NFE exome

AF:

0.0572

Gnomad4 OTH exome

AF:

0.0474

GnomAD4 genome

AF:

0.0377

AC:

5741

AN:

152310

Hom.:

147

Cov.:

AF XY:

0.0356

AC XY:

2648

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00993

Gnomad4 AMR

AF:

0.0420

Gnomad4 ASJ

AF:

0.0346

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0698

Gnomad4 FIN

AF:

0.0210

Gnomad4 NFE

AF:

0.0565

Gnomad4 OTH

AF:

0.0445

Alfa

AF:

0.0532

Hom.:

420

Bravo

AF:

0.0384

TwinsUK

AF:

0.0574

AC:

213

ALSPAC

AF:

0.0597

AC:

230

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.0573

AC:

493

ExAC

AF:

0.0475

AC:

5772

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0595

EpiControl

AF:

0.0626

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;.

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.29

PROVEAN

Pathogenic

-4.6

.;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

.;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.99

D;D

Vest4

0.33

MPC

0.22

ClinPred

0.042

GERP RS

3.8

Varity_R

0.30

gMVP

0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over