chr2-218830764-G-C

Variant names:

• chr2-218830764-G-C
• rs692243
• NM_017431.4:c.211C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017431.4(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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2132 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24386 hom.)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 28 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 -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG3	NM_017431.4	MANE Select	c.211C>G	p.Pro71Ala	missense	Exon 3 of 14	NP_059127.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG3	ENST00000439262.7	TSL:1 MANE Select	c.211C>G	p.Pro71Ala	missense	Exon 3 of 14	ENSP00000397133.3
	PRKAG3	ENST00000529249.6	TSL:1	c.211C>G	p.Pro71Ala	missense	Exon 3 of 13	ENSP00000436068.1
	PRKAG3	ENST00000430489.1	TSL:5	c.211C>G	p.Pro71Ala	missense	Exon 3 of 4	ENSP00000416100.1

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

GnomAD2 exomes AF: 0.183 AC: 45956 AN: 251358 AF XY: 0.183

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 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

African (AFR) AF: 0.0746 AC: 2493 AN: 33428

American (AMR) AF: 0.174 AC: 7796 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 6222 AN: 26132

East Asian (EAS) AF: 0.384 AC: 15226 AN: 39698

South Asian (SAS) AF: 0.171 AC: 14768 AN: 86178

European-Finnish (FIN) AF: 0.108 AC: 5785 AN: 53352

Middle Eastern (MID) AF: 0.175 AC: 772 AN: 4412

European-Non Finnish (NFE) AF: 0.175 AC: 194892 AN: 1111796

Other (OTH) AF: 0.182 AC: 10975 AN: 60234

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

African (AFR) AF: 0.0762 AC: 3162 AN: 41522

American (AMR) AF: 0.174 AC: 2661 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 862 AN: 3470

East Asian (EAS) AF: 0.413 AC: 2127 AN: 5148

South Asian (SAS) AF: 0.169 AC: 815 AN: 4826

European-Finnish (FIN) AF: 0.115 AC: 1220 AN: 10596

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11724 AN: 67978

Other (OTH) AF: 0.153 AC: 323 AN: 2110

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 v4.9

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
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.090
Sift	Benign	0.16	T
Sift4G	Benign	0.92	T
Polyphen		0.19	B
Vest4		0.24
MPC		0.059
ClinPred		0.0057	T
GERP RS		1.9
Varity_R		0.040
gMVP		0.050
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs692243; hg19: chr2-219695487; COSMIC: COSV52100829;