Genetic Variant ENST00000439262.7:c.417C>T (chr2-218830194-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The ENST00000439262.7(PRKAG3):c.417C>T(p.Phe139Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,614,072 control chromosomes in the GnomAD database, including 2,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.069 ( 1153 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 1026 hom. )

Consequence

PRKAG3
ENST00000439262.7 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.934

Publications

5 publications found

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP7

Synonymous conserved (PhyloP=0.934 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG3	NM_017431.4 link	c.417C>T	p.Phe139Phe	synonymous_variant	Exon 4 of 14		NP_059127.2	Q9UGI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG3	ENST00000439262.7 link	c.417C>T	p.Phe139Phe	synonymous_variant	Exon 4 of 14	1		ENSP00000397133.3		Q9UGI9-1

Frequencies

GnomAD3 genomes

AF:

0.0686

AC:

10440

AN:

152170

Hom.:

1149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0284

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.0493

GnomAD2 exomes

AF:

0.0184

AC:

4610

AN:

250300

AF XY:

0.0133

show subpopulations

Gnomad AFR exome

AF:

0.237

Gnomad AMR exome

AF:

0.0127

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000834

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.00738

AC:

10786

AN:

1461784

Hom.:

1026

Cov.:

AF XY:

0.00632

AC XY:

4598

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.243

AC:

8121

AN:

33480

American (AMR)

AF:

0.0147

AC:

657

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

355

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000672

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000444

AC:

494

AN:

1111998

Other (OTH)

AF:

0.0166

AC:

1003

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

563

1126

1690

2253

2816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0687

AC:

10468

AN:

152288

Hom.:

1153

Cov.:

AF XY:

0.0666

AC XY:

4957

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.236

AC:

9812

AN:

41542

American (AMR)

AF:

0.0283

AC:

433

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

68018

Other (OTH)

AF:

0.0488

AC:

103

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

418

836

1253

1671

2089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0272

Hom.:

562

Bravo

AF:

0.0787

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.9

(source)

DANN

Benign

0.74

PhyloP100

0.93

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over