rs35050588

chr2-218830154-G-Cchr2-218830154-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017431.4(PRKAG3):c.457C>G(p.Leu153Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,614,110 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (310 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (279 hom.)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.477

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015447438).
• BP6: Variant 2-218830154-G-C is Benign according to our data. Variant chr2-218830154-G-C is described in ClinVar as [Benign]. Clinvar id is 3037423.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG3	NM_017431.4	c.457C>G	p.Leu153Val	missense_variant	4/14	ENST00000439262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG3	ENST00000439262.7	c.457C>G	p.Leu153Val	missense_variant	4/14	1	NM_017431.4	P1
PRKAG3	ENST00000529249.5	c.457C>G	p.Leu153Val	missense_variant	4/13	1		P1
PRKAG3	ENST00000490971.1	n.490C>G		non_coding_transcript_exon_variant	4/9	2
PRKAG3	ENST00000470307.6	c.457C>G	p.Leu153Val	missense_variant, NMD_transcript_variant	4/11	5

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5283 AN: 152218 Hom.: 309 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.00895 AC: 2246 AN: 250942 Hom.: 124 AF XY: 0.00651 AC XY: 884 AN XY: 135718

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00668

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00351 AC: 5124 AN: 1461774 Hom.: 279 Cov.: 33 AF XY: 0.00300 AC XY: 2183 AN XY: 727172

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.00805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00902

GnomAD4 genome AF: 0.0347 AC: 5289 AN: 152336 Hom.: 310 Cov.: 32 AF XY: 0.0334 AC XY: 2486 AN XY: 74504

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0179

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.00267 Hom.: 8

Bravo AF: 0.0403

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.113 AC: 498

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0108 AC: 1310

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRKAG3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2019

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	0.056
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.1
Dann	Benign	0.75
DEOGEN2	Benign	0.049	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.16	T;.
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
REVEL	Benign	0.19
Sift4G	Benign	0.59	T;T
Polyphen		0.0	B;B
Vest4		0.043
MPC		0.051
ClinPred		0.0051	T
GERP RS		4.0
Varity_R		0.042
gMVP		0.10

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

Other links and lift over

dbSNP: rs35050588; hg19: chr2-219694877; COSMIC: COSV52102883; COSMIC: COSV52102883;