rs932447

Positions:

• chr1-56704556-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006252.4(PRKAA2):​c.1293+81T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,468,426 control chromosomes in the GnomAD database, including 142,408 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.

• Frequency:
  • Genomes: 𝑓 0.40 (12636 hom., cov: 32)
  • Exomes 𝑓: 0.44 (129772 hom.)
• Consequence: PRKAA2 NM_006252.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.627

Genes affected

PRKAA2 (HGNC:9377): (protein kinase AMP-activated catalytic subunit alpha 2) The protein encoded by this gene is a catalytic 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. Studies of the mouse counterpart suggest that this catalytic subunit may control whole-body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAA2	NM_006252.4	c.1293+81T>C		intron_variant		ENST00000371244.9
PRKAA2	XM_017001693.2	c.1023+81T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAA2	ENST00000371244.9	c.1293+81T>C		intron_variant		1	NM_006252.4	P1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60427 AN: 151854 Hom.: 12638 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.419

GnomAD4 exome AF: 0.438 AC: 576924 AN: 1316454 Hom.: 129772 AF XY: 0.435 AC XY: 281824 AN XY: 648002

Gnomad4 AFR exome AF: 0.328

Gnomad4 AMR exome AF: 0.287

Gnomad4 ASJ exome AF: 0.502

Gnomad4 EAS exome AF: 0.194

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.437

Gnomad4 NFE exome AF: 0.466

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.398 AC: 60430 AN: 151972 Hom.: 12636 Cov.: 32 AF XY: 0.391 AC XY: 29071 AN XY: 74286

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.415

Alfa AF: 0.450 Hom.: 25992

Bravo AF: 0.390

Asia WGS AF: 0.210 AC: 734 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.73

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: rs932447; hg19: chr1-57170229; COSMIC: COSV64802710;