Genetic Variant PRKAA2:p.Arg239Ser (chr1-56696086-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_006252.4(PRKAA2):c.715C>A(p.Arg239Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R239H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PRKAA2
NM_006252.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Publications

0 publications found

Variant links:

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]

PRKAA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3674397).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAA2	NM_006252.4	MANE Select	c.715C>A	p.Arg239Ser	missense	Exon 6 of 9	NP_006243.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRKAA2	ENST00000371244.9	TSL:1 MANE Select	c.715C>A	p.Arg239Ser	missense	Exon 6 of 9	ENSP00000360290.4	P54646
PRKAA2	ENST00000860136.1		c.715C>A	p.Arg239Ser	missense	Exon 6 of 9	ENSP00000530195.1
PRKAA2	ENST00000860138.1		c.563+2234C>A		intron	N/A	ENSP00000530197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

Eigen

Benign

-0.024

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

M_CAP

Benign

0.016

MetaRNN

Benign

0.37

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.22

PhyloP100

7.6

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

REVEL

Benign

0.29

Sift

Benign

0.31

Sift4G

Benign

0.43

Polyphen

0.020

Vest4

0.56

MutPred

0.43

Gain of phosphorylation at Y236 (P = 0.1682)

MVP

0.84

MPC

0.65

ClinPred

0.93

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.75

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over