2-218823787-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017431.4(PRKAG3):c.1445C>T(p.Ala482Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,614,120 control chromosomes in the GnomAD database, including 18 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 0.0057 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (12 hom.)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.28

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009650469).
• BP6: Variant 2-218823787-G-A is Benign according to our data. Variant chr2-218823787-G-A is described in ClinVar as [Benign]. Clinvar id is 3041896.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00574 (874/152324) while in subpopulation AFR AF= 0.0196 (814/41552). AF 95% confidence interval is 0.0185. There are 6 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 869 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG3	NM_017431.4	c.1445C>T	p.Ala482Val	missense_variant	13/14	ENST00000439262.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG3	ENST00000439262.7	c.1445C>T	p.Ala482Val	missense_variant	13/14	1	NM_017431.4	P1
PRKAG3	ENST00000529249.5	c.1445C>T	p.Ala482Val	missense_variant	13/13	1		P1

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 869 AN: 152206 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

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: 0.000103

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00164 AC: 412 AN: 251346 Hom.: 3 AF XY: 0.00119 AC XY: 161 AN XY: 135856

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000737 AC: 1077 AN: 1461796 Hom.: 12 Cov.: 31 AF XY: 0.000660 AC XY: 480 AN XY: 727200

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000962

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152324 Hom.: 6 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74490

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00120 Hom.: 2

Bravo AF: 0.00629

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00192 AC: 233

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

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 25, 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	0.29
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;.
MetaRNN	Benign	0.0097	T;T
MetaSVM	Uncertain	0.36	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
REVEL	Pathogenic	0.65
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.43
MVP		0.95
MPC		0.34
ClinPred		0.025	T
GERP RS		5.2
Varity_R		0.34
gMVP		0.79

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: rs34720726; hg19: chr2-219688510;