2-218827089-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_017431.4(PRKAG3):c.1007C>T(p.Ser336Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,613,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

PRKAG3
NM_017431.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.20

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011256844).

BP6

Variant 2-218827089-G-A is Benign according to our data. Variant chr2-218827089-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710901.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG3	NM_017431.4 linkuse as main transcript	c.1007C>T	p.Ser336Phe	missense_variant	10/14	ENST00000439262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG3	ENST00000439262.7 linkuse as main transcript	c.1007C>T	p.Ser336Phe	missense_variant	10/14	1	NM_017431.4	P1	Q9UGI9-1
PRKAG3	ENST00000529249.5 linkuse as main transcript	c.1007C>T	p.Ser336Phe	missense_variant	10/13	1		P1	Q9UGI9-1
PRKAG3	ENST00000490971.1 linkuse as main transcript	n.1165C>T		non_coding_transcript_exon_variant	9/9	2
PRKAG3	ENST00000470307.6 linkuse as main transcript	c.961C>T	p.Pro321Ser	missense_variant, NMD_transcript_variant	9/11	5

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000334

AC:

AN:

251456

Hom.:

AF XY:

0.000235

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00474

Gnomad AMR exome

AF:

0.000202

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1460864

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.00511

Gnomad4 AMR exome

AF:

0.000291

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152318

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.00138

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000395

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.36

T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;.

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.012

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Benign

0.34

REVEL

Uncertain

0.34

Sift4G

Benign

0.082

T;T

Polyphen

0.23

B;B

Vest4

0.24

MVP

0.90

MPC

0.088

ClinPred

0.052

GERP RS

4.9

Varity_R

0.14

gMVP

0.56

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