Variant 12-49005325-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002733.5(PRKAG1):c.290G>A(p.Arg97His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PRKAG1
NM_002733.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82

Variant links:

Genes affected

PRKAG1 (HGNC:9385): (protein kinase AMP-activated non-catalytic subunit gamma 1) The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This subunit is one of the gamma regulatory subunits of AMPK. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

PRKAG1 links:

ENSG00000288710 (HGNC:):

ENSG00000288710 links:

DDN-AS1 (HGNC:53464): (DDN and PRKAG1 antisense RNA 1)

DDN-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG1	NM_002733.5 link	c.290G>A	p.Arg97His	missense_variant	Exon 5 of 12	ENST00000548065.7	NP_002724.1	P54619-1A0A024R125

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PRKAG1	ENST00000548065.7 link	c.290G>A	p.Arg97His	missense_variant	Exon 5 of 12	1	NM_002733.5	ENSP00000447433.1	P54619-1
ENSG00000288710	ENST00000683988.1 link	n.*357G>A		non_coding_transcript_exon_variant	Exon 9 of 16			ENSP00000506939.1	A0A804HI77
ENSG00000288710	ENST00000683988.1 link	n.*357G>A		3_prime_UTR_variant	Exon 9 of 16			ENSP00000506939.1	A0A804HI77

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.317G>A (p.R106H) alteration is located in exon 5 (coding exon 5) of the PRKAG1 gene. This alteration results from a G to A substitution at nucleotide position 317, causing the arginine (R) at amino acid position 106 to be replaced by a histidine (H). 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

0.33

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;.;T;.;.;T;.;T;T;.;.;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.016

MutationAssessor

Uncertain

2.4

.;.;M;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.44

Sift

Benign

0.36

T;T;T;T;D;D;T;T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T;.;.;.;.;.;.;.

Polyphen

0.016

.;.;B;.;.;.;.;.;.;.;.;.

Vest4

0.89

MutPred

0.57

.;.;Gain of catalytic residue at L95 (P = 5e-04);.;.;.;.;.;.;.;.;.;

MVP

0.97

MPC

2.1

ClinPred

0.96

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.68

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over