1-56696120-A-T

Variant names:

• chr1-56696120-A-T
• rs534372739
• NM_006252.4:c.749A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006252.4(PRKAA2):​c.749A>T​(p.Gln250Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q250R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: PRKAA2 NM_006252.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.749A>T	p.Gln250Leu	missense	Exon 6 of 9	NP_006243.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAA2	ENST00000371244.9	TSL:1 MANE Select	c.749A>T	p.Gln250Leu	missense	Exon 6 of 9	ENSP00000360290.4	P54646
	PRKAA2	ENST00000860136.1		c.749A>T	p.Gln250Leu	missense	Exon 6 of 9	ENSP00000530195.1
	PRKAA2	ENST00000860138.1		c.563+2268A>T		intron	N/A	ENSP00000530197.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151742 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151742 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74062

African (AFR) AF: 0.00 AC: 0 AN: 41272

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.37
Sift	Benign	0.68	T
Sift4G	Benign	0.56	T
Polyphen		0.012	B
Vest4		0.75
MutPred		0.60		Loss of solvent accessibility (P = 0.0635)
MVP		0.80
MPC		0.57
ClinPred		0.96	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.77
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs534372739; hg19: chr1-57161793;