rs751094298

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_016203.4(PRKAG2):c.704T>G(p.Leu235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,408,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. L235P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.50

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12076059).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000535 (8/149620) while in subpopulation AFR AF= 0.000195 (8/41130). AF 95% confidence interval is 0.0000963. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.704T>G	p.Leu235Arg	missense_variant	5/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9 linkuse as main transcript	c.704T>G	p.Leu235Arg	missense_variant	5/16	1	NM_016203.4	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.0000535

AC:

AN:

149620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000184

AC:

AN:

163354

Hom.:

AF XY:

0.0000213

AC XY:

AN XY:

93772

show subpopulations

Gnomad AFR exome

AF:

0.000276

Gnomad AMR exome

AF:

0.0000421

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000715

AC:

AN:

1258914

Hom.:

Cov.:

AF XY:

0.00000480

AC XY:

AN XY:

625520

show subpopulations

Gnomad4 AFR exome

AF:

0.000268

Gnomad4 AMR exome

AF:

0.0000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000535

AC:

AN:

149620

Hom.:

Cov.:

AF XY:

0.0000685

AC XY:

AN XY:

72968

show subpopulations

Gnomad4 AFR

AF:

0.000195

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 04, 2023	This missense variant replaces leucine with arginine at codon 235 of the PRKAG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/191708 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 21, 2023	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2021

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#410720; Landrum et al., 2016) -

Wolff-Parkinson-White pattern;C1833236:Hypertrophic cardiomyopathy 6;C1849813:Lethal congenital glycogen storage disease of heart

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

PRKAG2 NM_016203.3 exon 5 p.Leu235Arg (c.704T>G): This variant has not been reported in the literature but is present in 0.04% (7/15616) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-151329205-A-C). This variant is present in ClinVar (Variation ID:410720). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2022

The p.L235R variant (also known as c.704T>G), located in coding exon 5 of the PRKAG2 gene, results from a T to G substitution at nucleotide position 704. The leucine at codon 235 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lethal congenital glycogen storage disease of heart

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

CardioboostCm

Uncertain

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Benign

0.57

DEOGEN2

Benign

0.050

T;.;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.47

T;T;T

M_CAP

Pathogenic

0.86

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

1.6

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.46

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.26

MutPred

0.44

Gain of methylation at L235 (P = 0.0214);.;.;

MVP

0.37

MPC

0.92

ClinPred

0.026

GERP RS

2.5

Varity_R

0.066

gMVP

0.48

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