rs12749128

Positions:

• chr1-56688704-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006252.4(PRKAA2):​c.237-2690A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 152,342 control chromosomes in the GnomAD database, including 26 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 0.017 (26 hom., cov: 32)
• Consequence: PRKAA2 NM_006252.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111

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=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2543/152342) while in subpopulation NFE AF= 0.0228 (1550/68026). AF 95% confidence interval is 0.0218. There are 26 homozygotes in gnomad4. There are 1304 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2543 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAA2	NM_006252.4	c.237-2690A>G		intron_variant		ENST00000371244.9	NP_006243.2
PRKAA2	XM_017001693.2	c.-34-2690A>G		intron_variant			XP_016857182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAA2	ENST00000371244.9	c.237-2690A>G		intron_variant		1	NM_006252.4	ENSP00000360290	P1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2542 AN: 152224 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0186

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

GnomAD4 genome AF: 0.0167 AC: 2543 AN: 152342 Hom.: 26 Cov.: 32 AF XY: 0.0175 AC XY: 1304 AN XY: 74498

Gnomad4 AFR AF: 0.00418

Gnomad4 AMR AF: 0.00934

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0220 Hom.: 8

Bravo AF: 0.0141

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.78

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: rs12749128; hg19: chr1-57154377;