5-40764774-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006251.6(PRKAA1):ā€‹c.1286A>Gā€‹(p.Lys429Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,611,886 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…).

Frequency

Genomes: š‘“ 0.00038 ( 4 hom., cov: 32)
Exomes š‘“: 0.00030 ( 13 hom. )

Consequence

PRKAA1
NM_006251.6 missense

Scores

2
4
13

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.67
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008815497).
BP6
Variant 5-40764774-T-C is Benign according to our data. Variant chr5-40764774-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 719129.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRKAA1NM_006251.6 linkuse as main transcriptc.1286A>G p.Lys429Arg missense_variant 7/9 ENST00000397128.7 NP_006242.5
LOC124900968XR_007058747.1 linkuse as main transcriptn.1451+307T>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.1286A>G p.Lys429Arg missense_variant 7/91 NM_006251.6 ENSP00000380317 P1Q13131-1
PRKAA1ENST00000354209.7 linkuse as main transcriptc.1331A>G p.Lys444Arg missense_variant 8/101 ENSP00000346148 Q13131-2
PRKAA1ENST00000505783.5 linkuse as main transcriptn.915A>G non_coding_transcript_exon_variant 4/42
PRKAA1ENST00000513152.1 linkuse as main transcriptn.15A>G non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
AF:
0.000361
AC:
55
AN:
152250
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000719
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00519
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000503
AC:
125
AN:
248686
Hom.:
0
AF XY:
0.000459
AC XY:
62
AN XY:
134934
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00618
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00133
GnomAD4 exome
AF:
0.000299
AC:
437
AN:
1459518
Hom.:
13
Cov.:
31
AF XY:
0.000251
AC XY:
182
AN XY:
725586
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00530
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00353
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152368
Hom.:
4
Cov.:
32
AF XY:
0.000268
AC XY:
20
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.000240
Gnomad4 AMR
AF:
0.000718
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00520
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.000756
Hom.:
6
Bravo
AF:
0.000514
ESP6500AA
AF:
0.000272
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000480
AC:
58
Asia WGS
AF:
0.00895
AC:
31
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 04, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;.
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.0088
T;T
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
2.0
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.27
Sift
Benign
0.14
T;T
Sift4G
Benign
0.24
T;T
Polyphen
0.0080
B;B
Vest4
0.59
MVP
0.82
MPC
0.42
ClinPred
0.040
T
GERP RS
6.0
Varity_R
0.37
gMVP
0.39

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: rs146544425; hg19: chr5-40764876; COSMIC: COSV57186189; COSMIC: COSV57186189; API