rs201953758

Positions:

chr7-151781367-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016203.4(PRKAG2):c.251G>A(p.Arg84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.83

Variant links:

Genes affected

PRKAG2 (HGNC:9386): (protein kinase AMP-activated non-catalytic subunit gamma 2) AMP-activated protein kinase (AMPK) is a heterotrimeric protein composed of a catalytic alpha subunit, a noncatalytic beta subunit, and a noncatalytic regulatory gamma subunit. Various forms of each of these subunits exist, encoded by different genes. AMPK is an important energy-sensing enzyme that monitors cellular energy status and functions by inactivating key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This gene is a member of the AMPK gamma subunit family. Mutations in this gene have been associated with Wolff-Parkinson-White syndrome, familial hypertrophic cardiomyopathy, and glycogen storage disease of the heart. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2015]

PRKAG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026867986).

BP6

Variant 7-151781367-C-T is Benign according to our data. Variant chr7-151781367-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45712.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000342 (52/152170) while in subpopulation AMR AF= 0.00268 (41/15288). AF 95% confidence interval is 0.00203. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.251G>A	p.Arg84Gln	missense_variant	3/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9 linkuse as main transcript	c.251G>A	p.Arg84Gln	missense_variant	3/16	1	NM_016203.4	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00269

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:

0.0000735

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000364

AC:

AN:

244742

Hom.:

AF XY:

0.000323

AC XY:

AN XY:

133304

show subpopulations

Gnomad AFR exome

AF:

0.0000666

Gnomad AMR exome

AF:

0.00189

Gnomad ASJ exome

AF:

0.000404

Gnomad EAS exome

AF:

0.000384

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000730

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000123

AC:

180

AN:

1460908

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00173

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000342

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.000329

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 19, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 11, 2012

Variant classified as Uncertain Significance - Favor Benign. The Arg84Gln varian t in PRKAG2 has not been reported in the literature, but has been identified in 2 Caucasian individuals with HCM tested by our laboratory, one of which carried a second pathogenic variant sufficient to explain disease. Arginine (Arg) at pos ition 84 is not completely conserved in mammals and several species (elephant, r ock hyrax, and tenrec) carry a glutamine (Gln; this variant), supporting that th is change may be tolerated. Additional computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Finally, this variant is outside the CBS domain (residu es 277-555) where all pathogenic PRKAG2 variants identified to date are located. In summary, the available information on the Arg84Gln variant supports that it may be benign, but additional studies are needed to fully assess its clinical si gnificance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Lethal congenital glycogen storage disease of heart

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

CardioboostCm

Benign

0.0039

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

0.89

N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.12

Sift

Benign

0.11

T;T

Sift4G

Benign

0.61

T;T

Polyphen

0.0030

B;.

Vest4

0.25

MutPred

0.19

Loss of methylation at R79 (P = 0.0873);.;

MVP

0.59

MPC

0.16

ClinPred

0.017

GERP RS

3.7

Varity_R

0.072

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over