5-40764774-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_006251.6(PRKAA1):c.1286A>G(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 (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (13 hom.)
• Consequence: PRKAA1 NM_006251.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.67

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]

LOC124900968 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PRKAA1
• 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 GnomAd at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAA1	NM_006251.6	c.1286A>G	p.Lys429Arg	missense_variant	7/9	ENST00000397128.7
LOC124900968	XR_007058747.1	n.1451+307T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAA1	ENST00000397128.7	c.1286A>G	p.Lys429Arg	missense_variant	7/9	1	NM_006251.6	P1
PRKAA1	ENST00000354209.7	c.1331A>G	p.Lys444Arg	missense_variant	8/10	1
PRKAA1	ENST00000505783.5	n.915A>G		non_coding_transcript_exon_variant	4/4	2
PRKAA1	ENST00000513152.1	n.15A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152250 Hom.: 4 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 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

Other links and lift over

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