NM_017431.4:c.1126G>A

Variant names:

• chr2-218826970-C-T
• NM_017431.4:c.1126G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017431.4(PRKAG3):​c.1126G>A​(p.Val376Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

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.1126G>A	p.Val376Met	missense	Exon 10 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.1126G>A	p.Val376Met	missense	Exon 10 of 14	ENSP00000397133.3	Q9UGI9-1
	PRKAG3	ENST00000529249.6	TSL:1	c.1126G>A	p.Val376Met	missense	Exon 10 of 13	ENSP00000436068.1
	PRKAG3	ENST00000470307.6	TSL:5	n.*18G>A		non_coding_transcript_exon	Exon 9 of 11	ENSP00000419272.2	B4DUK8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.57		Gain of phosphorylation at S381 (P = 0.2772)
MVP		0.96
MPC		0.34
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.74
Mutation Taster		=49/51	disease causing

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

hg19: chr2-219691693;