chr5-40763007-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006251.6(PRKAA1):ā€‹c.1451C>Gā€‹(p.Ala484Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 32)
Exomes š‘“: 0.000029 ( 0 hom. )

Consequence

PRKAA1
NM_006251.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.041775107).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRKAA1NM_006251.6 linkuse as main transcriptc.1451C>G p.Ala484Gly missense_variant 9/9 ENST00000397128.7 NP_006242.5
LOC124900968XR_007058747.1 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRKAA1ENST00000397128.7 linkuse as main transcriptc.1451C>G p.Ala484Gly missense_variant 9/91 NM_006251.6 ENSP00000380317 P1Q13131-1
PRKAA1ENST00000354209.7 linkuse as main transcriptc.1496C>G p.Ala499Gly missense_variant 10/101 ENSP00000346148 Q13131-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000769
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000688
AC:
17
AN:
246944
Hom.:
0
AF XY:
0.0000745
AC XY:
10
AN XY:
134176
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000556
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000294
AC:
43
AN:
1461676
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000403
Gnomad4 SAS exome
AF:
0.000186
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000770
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.0000414
AC:
5
Asia WGS
AF:
0.00231
AC:
8
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 12, 2023The c.1496C>G (p.A499G) alteration is located in exon 10 (coding exon 10) of the PRKAA1 gene. This alteration results from a C to G substitution at nucleotide position 1496, causing the alanine (A) at amino acid position 499 to be replaced by a glycine (G). 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
0.079
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.091
T;.
Eigen
Benign
-0.048
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.86
D;D
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.042
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;.
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
0.36
N;N
REVEL
Benign
0.084
Sift
Benign
0.36
T;T
Sift4G
Benign
0.36
T;T
Polyphen
0.031
B;B
Vest4
0.13
MutPred
0.15
Gain of relative solvent accessibility (P = 0.0479);.;
MVP
0.81
MPC
0.52
ClinPred
0.056
T
GERP RS
5.9
Varity_R
0.084
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371307629; hg19: chr5-40763109; API