2-218830071-G-A

Variant names:

• chr2-218830071-G-A
• rs35658907
• NM_017431.4:c.540C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_017431.4(PRKAG3):​c.540C>T​(p.Gly180Gly) 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
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3122 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG3	NM_017431.4	MANE Select	c.540C>T	p.Gly180Gly	synonymous	Exon 4 of 14	NP_059127.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG3	ENST00000439262.7	TSL:1 MANE Select	c.540C>T	p.Gly180Gly	synonymous	Exon 4 of 14	ENSP00000397133.3
	PRKAG3	ENST00000529249.6	TSL:1	c.540C>T	p.Gly180Gly	synonymous	Exon 4 of 13	ENSP00000436068.1
	PRKAG3	ENST00000470307.6	TSL:5	n.540C>T		non_coding_transcript_exon	Exon 4 of 11	ENSP00000419272.2

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

GnomAD2 exomes AF: 0.0216 AC: 5416 AN: 250866 AF XY: 0.0217

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 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

African (AFR) AF: 0.00370 AC: 124 AN: 33476

American (AMR) AF: 0.0135 AC: 603 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0270 AC: 706 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00659 AC: 568 AN: 86188

European-Finnish (FIN) AF: 0.0359 AC: 1915 AN: 53336

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5764

European-Non Finnish (NFE) AF: 0.0327 AC: 36329 AN: 1111624

Other (OTH) AF: 0.0246 AC: 1485 AN: 60370

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

African (AFR) AF: 0.00599 AC: 249 AN: 41562

American (AMR) AF: 0.0151 AC: 231 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4826

European-Finnish (FIN) AF: 0.0338 AC: 359 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0310 AC: 2111 AN: 68032

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0267 Hom.: 103

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.3
DANN	Benign	0.88
PhyloP100		-0.79
Mutation Taster		=297/3	polymorphism (auto)

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

Other links and lift over

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