Variant 12-49004581-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002733.5(PRKAG1):c.463G>A(p.Val155Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PRKAG1
NM_002733.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG1	NM_002733.5 link	c.463G>A	p.Val155Ile	missense_variant	Exon 8 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.463G>A	p.Val155Ile	missense_variant	Exon 8 of 12	1	NM_002733.5	ENSP00000447433.1	P54619-1
ENSG00000288710	ENST00000683988.1 link	n.*530G>A		non_coding_transcript_exon_variant	Exon 12 of 16			ENSP00000506939.1	A0A804HI77
ENSG00000288710	ENST00000683988.1 link	n.*530G>A		3_prime_UTR_variant	Exon 12 of 16			ENSP00000506939.1	A0A804HI77

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251472

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.490G>A (p.V164I) alteration is located in exon 8 (coding exon 8) of the PRKAG1 gene. This alteration results from a G to A substitution at nucleotide position 490, causing the valine (V) at amino acid position 164 to be replaced by an isoleucine (I). 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

0.17

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;.;D;.;.;T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.76

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

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.9

.;.;L;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.88

N;N;N;N;N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.11

T;T;T;T;T;T;T

Sift4G

Benign

0.10

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

Polyphen

0.65

.;.;P;.;.;.;.

Vest4

0.37

MutPred

0.55

.;.;Gain of catalytic residue at L153 (P = 0);.;.;.;.;

MVP

0.94

MPC

0.80

ClinPred

0.74

GERP RS

5.5

Varity_R

0.27

gMVP

0.57

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over