rs33985460

Variant names:

• chr2-218827078-G-A
• rs33985460
• ENST00000439262.7:c.1018C>T

Variant summary

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

The ENST00000439262.7(PRKAG3):​c.1018C>T​(p.Arg340Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0522 in 1,613,264 control chromosomes in the GnomAD database, including 2,583 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R340Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (147 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2436 hom.)
• Consequence: PRKAG3 ENST00000439262.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.91
• Publications: 13 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=0.0076971054).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG3	NM_017431.4	c.1018C>T	p.Arg340Trp	missense_variant	Exon 10 of 14		NP_059127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG3	ENST00000439262.7	c.1018C>T	p.Arg340Trp	missense_variant	Exon 10 of 14	1		ENSP00000397133.3
PRKAG3	ENST00000529249.6	c.1018C>T	p.Arg340Trp	missense_variant	Exon 10 of 13	1		ENSP00000436068.1
PRKAG3	ENST00000470307.6	n.972C>T		non_coding_transcript_exon_variant	Exon 9 of 11	5		ENSP00000419272.2
PRKAG3	ENST00000490971.1	n.1176C>T		non_coding_transcript_exon_variant	Exon 9 of 9	2

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 5741 AN: 152192 Hom.: 147 Cov.: 32

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0421

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.0565

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0472 AC: 11858 AN: 251442 AF XY: 0.0500

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.0487

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0566

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0537 AC: 78454 AN: 1460954 Hom.: 2436 Cov.: 34 AF XY: 0.0548 AC XY: 39856 AN XY: 726794

African (AFR) AF: 0.00974 AC: 326 AN: 33458

American (AMR) AF: 0.0483 AC: 2158 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 996 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.0780 AC: 6721 AN: 86208

European-Finnish (FIN) AF: 0.0250 AC: 1337 AN: 53418

Middle Eastern (MID) AF: 0.0910 AC: 458 AN: 5032

European-Non Finnish (NFE) AF: 0.0572 AC: 63586 AN: 1111976

Other (OTH) AF: 0.0474 AC: 2857 AN: 60302

GnomAD4 genome AF: 0.0377 AC: 5741 AN: 152310 Hom.: 147 Cov.: 32 AF XY: 0.0356 AC XY: 2648 AN XY: 74472

African (AFR) AF: 0.00993 AC: 413 AN: 41572

American (AMR) AF: 0.0420 AC: 643 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0698 AC: 337 AN: 4828

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10618

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0565 AC: 3845 AN: 68012

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0510 Hom.: 820

Bravo AF: 0.0384

TwinsUK AF: 0.0574 AC: 213

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.0573 AC: 493

ExAC AF: 0.0475 AC: 5772

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.0595

EpiControl AF: 0.0626

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.4	L;L
PhyloP100		3.9
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.6	.;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	.;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	D;D
Vest4		0.33
MPC		0.22
ClinPred		0.042	T
GERP RS		3.8
Varity_R		0.30
gMVP		0.57
Mutation Taster		=93/7	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: rs33985460; hg19: chr2-219691801; COSMIC: COSV52101939; COSMIC: COSV52101939;