2-218823779-C-T

Variant names:

• chr2-218823779-C-T
• rs149508864
• NM_017431.4:c.1453G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (17 hom.)
• Consequence: PRKAG3 NM_017431.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.66
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -9 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 VariationId is 3052939.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 372 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG3	NM_017431.4	MANE Select	c.1453G>A	p.Asp485Asn	missense	Exon 13 of 14	NP_059127.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG3	ENST00000439262.7	TSL:1 MANE Select	c.1453G>A	p.Asp485Asn	missense	Exon 13 of 14	ENSP00000397133.3	Q9UGI9-1
	PRKAG3	ENST00000529249.6	TSL:1	c.1453G>A	p.Asp485Asn	missense	Exon 13 of 13	ENSP00000436068.1

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

GnomAD2 exomes AF: 0.00342 AC: 859 AN: 251326 AF XY: 0.00363

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 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

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00427 AC: 368 AN: 86258

European-Finnish (FIN) AF: 0.00709 AC: 378 AN: 53326

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00337 AC: 3742 AN: 1111990

Other (OTH) AF: 0.00306 AC: 185 AN: 60396

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

African (AFR) AF: 0.000529 AC: 22 AN: 41572

American (AMR) AF: 0.00222 AC: 34 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00537 AC: 57 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00284 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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PRKAG3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.19	D
PhyloP100		3.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.32
Sift	Benign	0.058	T
Sift4G	Benign	0.19	T
Polyphen		1.0	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
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs149508864; hg19: chr2-219688502;