chr5-40765179-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006251.6(PRKAA1):ā€‹c.881A>Gā€‹(p.Tyr294Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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‘“: 0.000043 ( 0 hom. )

Consequence

PRKAA1
NM_006251.6 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.60
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 Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.35644084).
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.881A>G p.Tyr294Cys missense_variant 7/9 ENST00000397128.7 NP_006242.5
LOC124900968XR_007058747.1 linkuse as main transcriptn.1451+712T>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.881A>G p.Tyr294Cys missense_variant 7/91 NM_006251.6 ENSP00000380317 P1Q13131-1
PRKAA1ENST00000354209.7 linkuse as main transcriptc.926A>G p.Tyr309Cys missense_variant 8/101 ENSP00000346148 Q13131-2
PRKAA1ENST00000505783.5 linkuse as main transcriptn.510A>G non_coding_transcript_exon_variant 4/42
PRKAA1ENST00000506652.5 linkuse as main transcriptn.840A>G non_coding_transcript_exon_variant 7/75

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000189
AC:
47
AN:
249306
Hom.:
0
AF XY:
0.000185
AC XY:
25
AN XY:
135254
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000956
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000425
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000431
AC:
63
AN:
1461602
Hom.:
0
Cov.:
31
AF XY:
0.0000509
AC XY:
37
AN XY:
727144
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000850
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000243
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152328
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000567
ExAC
AF:
0.000166
AC:
20
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 GeneticsMay 12, 2024The c.926A>G (p.Y309C) 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 926, causing the tyrosine (Y) at amino acid position 309 to be replaced by a cysteine (C). 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
0.14
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.0
D;D
REVEL
Uncertain
0.32
Sift
Benign
0.057
T;T
Sift4G
Benign
0.18
T;T
Polyphen
1.0
D;D
Vest4
0.77
MutPred
0.39
Loss of phosphorylation at Y294 (P = 0.0091);.;
MVP
0.89
MPC
1.5
ClinPred
0.16
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.50
gMVP
0.73

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: rs542464918; hg19: chr5-40765281; API