rs1418442

Positions:

• chr1-56693463-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.476-302T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,936 control chromosomes in the GnomAD database, including 11,419 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 0.37 (11419 hom., cov: 32)
• Consequence: PRKAA2 NM_006252.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.03

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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAA2	NM_006252.4	c.476-302T>C		intron_variant		ENST00000371244.9	NP_006243.2
PRKAA2	XM_017001693.2	c.206-302T>C		intron_variant			XP_016857182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAA2	ENST00000371244.9	c.476-302T>C		intron_variant		1	NM_006252.4	ENSP00000360290.4

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56435 AN: 151818 Hom.: 11419 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.402

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.371 AC: 56427 AN: 151936 Hom.: 11419 Cov.: 32 AF XY: 0.366 AC XY: 27154 AN XY: 74260

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.398

Alfa AF: 0.443 Hom.: 14524

Bravo AF: 0.360

Asia WGS AF: 0.206 AC: 714 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.4
DANN	Benign	0.77

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: rs1418442; hg19: chr1-57159136; COSMIC: COSV64802965;