2-218823779-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_017431.4(PRKAG3):c.1453G>A(p.Asp485Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00321 in 1,614,086 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (17 hom.)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.66

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008361936).
• BP6: Variant 2-218823779-C-T is Benign according to our data. Variant chr2-218823779-C-T is described in ClinVar as [Benign]. Clinvar id is 3052939.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 371 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG3	NM_017431.4	c.1453G>A	p.Asp485Asn	missense_variant	13/14	ENST00000439262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG3	ENST00000439262.7	c.1453G>A	p.Asp485Asn	missense_variant	13/14	1	NM_017431.4	P1
PRKAG3	ENST00000529249.5	c.1453G>A	p.Asp485Asn	missense_variant	13/13	1		P1

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00342 AC: 859 AN: 251326 Hom.: 7 AF XY: 0.00363 AC XY: 493 AN XY: 135844

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00421

Gnomad FIN exome AF: 0.00720

Gnomad NFE exome AF: 0.00434

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00329 AC: 4804 AN: 1461776 Hom.: 17 Cov.: 31 AF XY: 0.00337 AC XY: 2447 AN XY: 727186

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00427

Gnomad4 FIN exome AF: 0.00709

Gnomad4 NFE exome AF: 0.00337

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74466

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.00334

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00290 Hom.: 1

Bravo AF: 0.00230

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00365 AC: 443

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRKAG3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0084	T;T
MetaSVM	Uncertain	0.19	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
REVEL	Uncertain	0.32
Sift4G	Benign	0.19	T;T
Polyphen		1.0	D;D
Vest4		0.32
MVP		0.89
MPC		0.11
ClinPred		0.019	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.72

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: rs149508864; hg19: chr2-219688502;