12-49003186-A-T

Position:

chr12-49003186-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000548065.7(PRKAG1):c.846T>A(p.His282Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

PRKAG1
ENST00000548065.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.45

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:

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

DDN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20070487).

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG1	NM_002733.5 linkuse as main transcript	c.846T>A	p.His282Gln	missense_variant	11/12	ENST00000548065.7	NP_002724.1
DDN-AS1	NR_147178.1 linkuse as main transcript	n.344+4496A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG1	ENST00000548065.7 linkuse as main transcript	c.846T>A	p.His282Gln	missense_variant	11/12	1	NM_002733.5	ENSP00000447433	P4	P54619-1
DDN-AS1	ENST00000552933.2 linkuse as main transcript	n.324+4496A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251482

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000335

AC:

490

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000304

AC XY:

221

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000431

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000125

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

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 submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.873T>A (p.H291Q) alteration is located in exon 11 (coding exon 11) of the PRKAG1 gene. This alteration results from a T to A substitution at nucleotide position 873, causing the histidine (H) at amino acid position 291 to be replaced by a glutamine (Q). 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

0.21

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

8.3

DANN

Benign

0.90

DEOGEN2

Benign

0.39

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

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.62

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

M_CAP

Benign

0.049

MetaRNN

Benign

0.20

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

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.5

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.96

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

REVEL

Uncertain

0.54

Sift

Benign

0.31

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

Sift4G

Benign

0.58

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

Polyphen

0.031

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

Vest4

0.24, 0.29, 0.24, 0.23

MutPred

0.32

.;.;.;Gain of catalytic residue at H282 (P = 0.0101);.;.;.;

MVP

0.84

MPC

0.57

ClinPred

0.048

GERP RS

0.14

Varity_R

0.31

gMVP

0.52

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