Variant chr2-218827072-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017431.4(PRKAG3):c.1024T>G(p.Ser342Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PRKAG3
NM_017431.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.135

Variant links:

Genes affected

PRKAG3 (HGNC:9387): (protein kinase AMP-activated non-catalytic subunit gamma 3) 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. It is dominantly expressed in skeletal muscle. Studies of the pig counterpart suggest that this subunit may play a key role in the regulation of energy metabolism in skeletal muscle. [provided by RefSeq, Jul 2008]

PRKAG3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05898121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG3	NM_017431.4 linkuse as main transcript	c.1024T>G	p.Ser342Ala	missense_variant	10/14	ENST00000439262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG3	ENST00000439262.7 linkuse as main transcript	c.1024T>G	p.Ser342Ala	missense_variant	10/14	1	NM_017431.4	P1	Q9UGI9-1
PRKAG3	ENST00000529249.5 linkuse as main transcript	c.1024T>G	p.Ser342Ala	missense_variant	10/13	1		P1	Q9UGI9-1
PRKAG3	ENST00000490971.1 linkuse as main transcript	n.1182T>G		non_coding_transcript_exon_variant	9/9	2
PRKAG3	ENST00000470307.6 linkuse as main transcript	c.978T>G	p.Pro326=	synonymous_variant, NMD_transcript_variant	9/11	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461162

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726904

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:

0.00

Gnomad4 OTH exome

AF:

0.0000332

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.1024T>G (p.S342A) alteration is located in exon 10 (coding exon 10) of the PRKAG3 gene. This alteration results from a T to G substitution at nucleotide position 1024, causing the serine (S) at amino acid position 342 to be replaced by an alanine (A). 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

0.068

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.073

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.47

T;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.020

N;N

MutationTaster

Benign

0.63

D;N;N;N

PrimateAI

Benign

0.38

REVEL

Benign

0.14

Sift4G

Benign

0.77

T;T

Polyphen

0.011

B;B

Vest4

0.15

MutPred

0.30

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.63

MPC

0.046

ClinPred

0.050

GERP RS

0.76

Varity_R

0.054

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

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