chr2-218830154-G-C

Variant names:

• chr2-218830154-G-C
• rs35050588
• NM_017431.4:c.457C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_017431.4(PRKAG3):​c.457C>G​(p.Leu153Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,614,110 control chromosomes in the GnomAD database, including 589 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.035 (310 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (279 hom.)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.477
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015447438).
• BP6: Variant 2-218830154-G-C is Benign according to our data. Variant chr2-218830154-G-C is described in ClinVar as Benign. ClinVar VariationId is 3037423.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 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.457C>G	p.Leu153Val	missense	Exon 4 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.457C>G	p.Leu153Val	missense	Exon 4 of 14	ENSP00000397133.3	Q9UGI9-1
	PRKAG3	ENST00000529249.6	TSL:1	c.457C>G	p.Leu153Val	missense	Exon 4 of 13	ENSP00000436068.1
	PRKAG3	ENST00000470307.6	TSL:5	n.457C>G		non_coding_transcript_exon	Exon 4 of 11	ENSP00000419272.2	B4DUK8

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5283 AN: 152218 Hom.: 309 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.00895 AC: 2246 AN: 250942 AF XY: 0.00651

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00668

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00351 AC: 5124 AN: 1461774 Hom.: 279 Cov.: 33 AF XY: 0.00300 AC XY: 2183 AN XY: 727172

African (AFR) AF: 0.120 AC: 4007 AN: 33480

American (AMR) AF: 0.00805 AC: 360 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.000151 AC: 168 AN: 1111964

Other (OTH) AF: 0.00902 AC: 545 AN: 60392

GnomAD4 genome AF: 0.0347 AC: 5289 AN: 152336 Hom.: 310 Cov.: 32 AF XY: 0.0334 AC XY: 2486 AN XY: 74504

African (AFR) AF: 0.119 AC: 4926 AN: 41554

American (AMR) AF: 0.0179 AC: 274 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68034

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.00267 Hom.: 8

Bravo AF: 0.0403

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.113 AC: 498

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0108 AC: 1310

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PRKAG3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.1
DANN	Benign	0.75
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.48
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.051
ClinPred		0.0051	T
GERP RS		4.0
Varity_R		0.042
gMVP		0.10
Mutation Taster		=291/9	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: rs35050588; hg19: chr2-219694877; COSMIC: COSV52102883; COSMIC: COSV52102883;