chr5-40762869-G-A

Variant summary

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

The NM_006251.6(PRKAA1):​c.1589C>T​(p.Ser530Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,076 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PRKAA1
NM_006251.6 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.23
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=0.28091258).
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRKAA1NM_006251.6 linkuse as main transcriptc.1589C>T p.Ser530Phe missense_variant 9/9 ENST00000397128.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRKAA1ENST00000397128.7 linkuse as main transcriptc.1589C>T p.Ser530Phe missense_variant 9/91 NM_006251.6 P1Q13131-1
PRKAA1ENST00000354209.7 linkuse as main transcriptc.1634C>T p.Ser545Phe missense_variant 10/101 Q13131-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249422
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135342
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461862
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00

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 GeneticsAug 28, 2023The c.1634C>T (p.S545F) alteration is located in exon 10 (coding exon 10) of the PRKAA1 gene. This alteration results from a C to T substitution at nucleotide position 1634, causing the serine (S) at amino acid position 545 to be replaced by a phenylalanine (F). 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
0.10
BayesDel_addAF
Uncertain
0.038
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
0.34
N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.72
N;N
REVEL
Benign
0.26
Sift
Uncertain
0.024
D;D
Sift4G
Uncertain
0.053
T;T
Polyphen
0.97
D;D
Vest4
0.15
MutPred
0.27
Loss of glycosylation at S530 (P = 0.018);.;
MVP
0.88
MPC
1.3
ClinPred
0.59
D
GERP RS
5.9
Varity_R
0.20
gMVP
0.64

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: rs1394656931; hg19: chr5-40762971; API