2-218824361-G-T

Variant names:

• chr2-218824361-G-T
• rs950043181
• ENST00000439262.7:c.1214C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017431.4(PRKAG3):​c.1214C>A​(p.Ala405Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.05

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG3	NM_017431.4	c.1214C>A	p.Ala405Asp	missense_variant	Exon 12 of 14		NP_059127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG3	ENST00000439262.7	c.1214C>A	p.Ala405Asp	missense_variant	Exon 12 of 14	1		ENSP00000397133.3
PRKAG3	ENST00000529249.5	c.1214C>A	p.Ala405Asp	missense_variant	Exon 12 of 13	1		ENSP00000436068.1
PRKAG3	ENST00000470307.6	n.*106C>A		downstream_gene_variant		5		ENSP00000419272.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.82		Gain of phosphorylation at Y410 (P = 0.1432);Gain of phosphorylation at Y410 (P = 0.1432);
MVP		0.99
MPC		0.40
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs950043181; hg19: chr2-219689084;