1-56674397-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_006252.4(PRKAA2):c.111A>G(p.Leu37=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,559,532 control chromosomes in the GnomAD database, including 1,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (71 hom., cov: 33)
  • Exomes 𝑓: 0.035 (995 hom.)
• Consequence: PRKAA2 NM_006252.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.48

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-56674397-A-G is Benign according to our data. Variant chr1-56674397-A-G is described in ClinVar as [Benign]. Clinvar id is 3056337.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0249 (3790/152196) while in subpopulation NFE AF= 0.0372 (2529/67954). AF 95% confidence interval is 0.036. There are 71 homozygotes in gnomad4. There are 1840 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 3792 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAA2	NM_006252.4	c.111A>G	p.Leu37=	synonymous_variant	2/9	ENST00000371244.9
PRKAA2	XM_017001693.2	c.-160A>G		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAA2	ENST00000371244.9	c.111A>G	p.Leu37=	synonymous_variant	2/9	1	NM_006252.4	P1

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3792 AN: 152078 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.00712

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0372

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0268 AC: 5591 AN: 208508 Hom.: 96 AF XY: 0.0278 AC XY: 3165 AN XY: 113962

Gnomad AFR exome AF: 0.00604

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.000201

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.0300

Gnomad NFE exome AF: 0.0358

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0345 AC: 48595 AN: 1407336 Hom.: 995 Cov.: 30 AF XY: 0.0342 AC XY: 23900 AN XY: 699300

Gnomad4 AFR exome AF: 0.00651

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.0287

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.0231

Gnomad4 FIN exome AF: 0.0309

Gnomad4 NFE exome AF: 0.0381

Gnomad4 OTH exome AF: 0.0339

GnomAD4 genome AF: 0.0249 AC: 3790 AN: 152196 Hom.: 71 Cov.: 33 AF XY: 0.0247 AC XY: 1840 AN XY: 74422

Gnomad4 AFR AF: 0.00708

Gnomad4 AMR AF: 0.0247

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.0284

Gnomad4 NFE AF: 0.0372

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0321 Hom.: 44

Bravo AF: 0.0236

Asia WGS AF: 0.00783 AC: 27 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRKAA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.1
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs55717918; hg19: chr1-57140070; COSMIC: COSV64805381;