rs692243

Positions:

• chr2-218830764-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000439262.7(PRKAG3):​c.211C>G​(p.Pro71Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,612,086 control chromosomes in the GnomAD database, including 26,518 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2132 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24386 hom.)
• Consequence: PRKAG3 ENST00000439262.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016830862).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG3	NM_017431.4	c.211C>G	p.Pro71Ala	missense_variant	3/14	ENST00000439262.7	NP_059127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG3	ENST00000439262.7	c.211C>G	p.Pro71Ala	missense_variant	3/14	1	NM_017431.4	ENSP00000397133	P1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23062 AN: 152016 Hom.: 2124 Cov.: 32

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.183 AC: 45956 AN: 251358 Hom.: 5080 AF XY: 0.183 AC XY: 24867 AN XY: 135846

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.447

Gnomad SAS exome AF: 0.168

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.177 AC: 258929 AN: 1459952 Hom.: 24386 Cov.: 34 AF XY: 0.178 AC XY: 128994 AN XY: 726276

Gnomad4 AFR exome AF: 0.0746

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.384

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.152 AC: 23087 AN: 152134 Hom.: 2132 Cov.: 32 AF XY: 0.151 AC XY: 11235 AN XY: 74366

Gnomad4 AFR AF: 0.0762

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.413

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.153

Alfa AF: 0.173 Hom.: 810

Bravo AF: 0.154

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.0828 AC: 365

ESP6500EA AF: 0.178 AC: 1532

ExAC AF: 0.178 AC: 21653

Asia WGS AF: 0.274 AC: 950 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.178

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T;.;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.96	.;N;D
REVEL	Benign	0.090
Sift	Benign	0.16	.;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.19	B;B;.
Vest4		0.24
MPC		0.059
ClinPred		0.0057	T
GERP RS		1.9
Varity_R		0.040
gMVP		0.050

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs692243; hg19: chr2-219695487; COSMIC: COSV52100829;