rs35658907

chr2-218830071-G-Achr2-218830071-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_017431.4(PRKAG3):c.540C>T(p.Gly180=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,613,550 control chromosomes in the GnomAD database, including 725 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 32)
  • Exomes 𝑓: 0.029 (676 hom.)
• Consequence: PRKAG3 NM_017431.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=-0.792 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0205 (3122/152310) while in subpopulation NFE AF= 0.031 (2111/68032). AF 95% confidence interval is 0.0299. There are 49 homozygotes in gnomad4. There are 1434 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG3	NM_017431.4	c.540C>T	p.Gly180=	synonymous_variant	4/14	ENST00000439262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG3	ENST00000439262.7	c.540C>T	p.Gly180=	synonymous_variant	4/14	1	NM_017431.4	P1
PRKAG3	ENST00000529249.5	c.540C>T	p.Gly180=	synonymous_variant	4/13	1		P1
PRKAG3	ENST00000490971.1	n.573C>T		non_coding_transcript_exon_variant	4/9	2
PRKAG3	ENST00000470307.6	c.540C>T	p.Gly180=	synonymous_variant, NMD_transcript_variant	4/11	5

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3122 AN: 152192 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0338

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0310

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0216 AC: 5416 AN: 250866 Hom.: 84 AF XY: 0.0217 AC XY: 2942 AN XY: 135526

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00603

Gnomad FIN exome AF: 0.0353

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0286 AC: 41800 AN: 1461240 Hom.: 676 Cov.: 33 AF XY: 0.0279 AC XY: 20285 AN XY: 726808

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0270

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00659

Gnomad4 FIN exome AF: 0.0359

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0246

GnomAD4 genome AF: 0.0205 AC: 3122 AN: 152310 Hom.: 49 Cov.: 32 AF XY: 0.0193 AC XY: 1434 AN XY: 74480

Gnomad4 AFR AF: 0.00599

Gnomad4 AMR AF: 0.0151

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0338

Gnomad4 NFE AF: 0.0310

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0229 Hom.: 20

Bravo AF: 0.0189

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0296

EpiControl AF: 0.0335

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	7.3
Dann	Benign	0.88

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: rs35658907; hg19: chr2-219694794; COSMIC: COSV52104218; COSMIC: COSV52104218;