5-40762940-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006251.6(PRKAA1):c.1518T>G(p.Ser506Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PRKAA1 NM_006251.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.878

Genes affected

PRKAA1 (HGNC:9376): (protein kinase AMP-activated catalytic subunit alpha 1) The protein encoded by this gene belongs to the ser/thr protein kinase family. It is the catalytic subunit of the 5'-prime-AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor conserved in all eukaryotic cells. The kinase activity of AMPK is activated by the stimuli that increase the cellular AMP/ATP ratio. AMPK regulates the activities of a number of key metabolic enzymes through phosphorylation. It protects cells from stresses that cause ATP depletion by switching off ATP-consuming biosynthetic pathways. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PRKAA1
• BP4: Computational evidence support a benign effect (MetaRNN=0.12277603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAA1	NM_006251.6	c.1518T>G	p.Ser506Arg	missense_variant	9/9	ENST00000397128.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAA1	ENST00000397128.7	c.1518T>G	p.Ser506Arg	missense_variant	9/9	1	NM_006251.6	P1
PRKAA1	ENST00000354209.7	c.1563T>G	p.Ser521Arg	missense_variant	10/10	1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151892 Hom.: 0 Cov.: 32

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: 0.00000658 AC: 1 AN: 151892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74180

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.1563T>G (p.S521R) alteration is located in exon 10 (coding exon 10) of the PRKAA1 gene. This alteration results from a T to G substitution at nucleotide position 1563, causing the serine (S) at amino acid position 521 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.80	N;N
REVEL	Benign	0.042
Sift	Benign	0.26	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.38	B;P
Vest4		0.15
MutPred		0.22		Loss of phosphorylation at S506 (P = 0.0084);.;
MVP		0.78
MPC		0.92
ClinPred		0.60	D
GERP RS		-0.64
Varity_R		0.081
gMVP		0.23

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: rs1249689552; hg19: chr5-40763042;