Variant chr2-218830154-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017431.4(PRKAG3):c.457C>A(p.Leu153Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,614,120 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L153V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

PRKAG3
NM_017431.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.477

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:

PRKAG3 (HGNC:):

PRKAG3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013625771).

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG3	NM_017431.4 linkuse as main transcript	c.457C>A	p.Leu153Met	missense_variant	4/14		NP_059127.2	Q9UGI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
PRKAG3	ENST00000439262.7 linkuse as main transcript	c.457C>A	p.Leu153Met	missense_variant	4/14	1	ENSP00000397133.3	Q9UGI9-1
PRKAG3	ENST00000529249.5 linkuse as main transcript	c.457C>A	p.Leu153Met	missense_variant	4/13	1	ENSP00000436068.1	Q9UGI9-1
PRKAG3	ENST00000470307.6 linkuse as main transcript	n.457C>A		non_coding_transcript_exon_variant	4/11	5	ENSP00000419272.2	B4DUK8
PRKAG3	ENST00000490971.1 linkuse as main transcript	n.490C>A		non_coding_transcript_exon_variant	4/9	2

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000347

AC:

AN:

250942

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.000224

AC:

327

AN:

1461774

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

157

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000166

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000545

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000342

Hom.:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.076

T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.27

T;.

M_CAP

Benign

0.076

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.13

.;N

REVEL

Benign

0.15

Sift

Benign

0.037

.;D

Sift4G

Benign

0.24

T;T

Polyphen

0.0030

B;B

Vest4

0.11

MVP

0.72

MPC

0.050

ClinPred

0.0027

GERP RS

4.0

Varity_R

0.071

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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