5-40764900-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006251.6(PRKAA1):ā€‹c.1160A>Gā€‹(p.His387Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,614,098 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 32)
Exomes š‘“: 0.00014 ( 0 hom. )

Consequence

PRKAA1
NM_006251.6 missense

Scores

1
3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.00
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 -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.019779563).
BP6
Variant 5-40764900-T-C is Benign according to our data. Variant chr5-40764900-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 764979.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRKAA1NM_006251.6 linkuse as main transcriptc.1160A>G p.His387Arg missense_variant 7/9 ENST00000397128.7 NP_006242.5
LOC124900968XR_007058747.1 linkuse as main transcriptn.1451+433T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRKAA1ENST00000397128.7 linkuse as main transcriptc.1160A>G p.His387Arg missense_variant 7/91 NM_006251.6 ENSP00000380317 P1Q13131-1
PRKAA1ENST00000354209.7 linkuse as main transcriptc.1205A>G p.His402Arg missense_variant 8/101 ENSP00000346148 Q13131-2
PRKAA1ENST00000505783.5 linkuse as main transcriptn.789A>G non_coding_transcript_exon_variant 4/42
PRKAA1ENST00000506652.5 linkuse as main transcript downstream_gene_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00461
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000241
AC:
60
AN:
249428
Hom.:
0
AF XY:
0.000288
AC XY:
39
AN XY:
135338
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00447
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000137
AC:
200
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.000142
AC XY:
103
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00501
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00461
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000698
Hom.:
0
Bravo
AF:
0.000117
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.000132
AC:
16
EpiCase
AF:
0.000109
EpiControl
AF:
0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 02, 2024The c.1205A>G (p.H402R) alteration is located in exon 8 (coding exon 8) of the PRKAA1 gene. This alteration results from a A to G substitution at nucleotide position 1205, causing the histidine (H) at amino acid position 402 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 16, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.090
T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.020
T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
1.5
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.22
N;N
REVEL
Benign
0.22
Sift
Benign
0.39
T;T
Sift4G
Benign
0.69
T;T
Polyphen
0.89
P;P
Vest4
0.34
MVP
0.86
MPC
1.0
ClinPred
0.12
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.52

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

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

Other links and lift over

dbSNP: rs201118044; hg19: chr5-40765002; API