Genetic Variant PRKAG3:p.Asp485Asn (chr2-218823779-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017431.4(PRKAG3):c.1453G>A(p.Asp485Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00321 in 1,614,086 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 17 hom. )

Consequence

PRKAG3
NM_017431.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.66

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008361936).

BP6

Variant 2-218823779-C-T is Benign according to our data. Variant chr2-218823779-C-T is described in ClinVar as [Benign]. Clinvar id is 3052939.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 372 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG3	NM_017431.4 link	c.1453G>A	p.Asp485Asn	missense_variant	Exon 13 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.1453G>A	p.Asp485Asn	missense_variant	Exon 13 of 14	1		ENSP00000397133.3		Q9UGI9-1
PRKAG3	ENST00000529249.5 link	c.1453G>A	p.Asp485Asn	missense_variant	Exon 13 of 13	1		ENSP00000436068.1		Q9UGI9-1

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

371

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00537

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00334

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00342

AC:

859

AN:

251326

Hom.:

AF XY:

0.00363

AC XY:

493

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00421

Gnomad FIN exome

AF:

0.00720

Gnomad NFE exome

AF:

0.00434

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00329

AC:

4804

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

2447

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00427

Gnomad4 FIN exome

AF:

0.00709

Gnomad4 NFE exome

AF:

0.00337

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.00244

AC:

372

AN:

152310

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00537

Gnomad4 NFE

AF:

0.00334

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00290

Hom.:

Bravo

AF:

0.00230

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00365

AC:

443

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PRKAG3-related disorder

Benign:1

Nov 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.90

D;.

M_CAP

Benign

0.060

MetaRNN

Benign

0.0084

T;T

MetaSVM

Uncertain

0.19

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.8

.;N

REVEL

Uncertain

0.32

Sift

Benign

0.058

.;T

Sift4G

Benign

0.19

T;T

Polyphen

1.0

D;D

Vest4

0.32

MVP

0.89

MPC

0.11

ClinPred

0.019

GERP RS

5.2

Varity_R

0.12

gMVP

0.72

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over