rs41317142

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_016203.4(PRKAG2):c.593C>T(p.Pro198Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P198R) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:1

Conservation

PhyloP100: 4.36

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17343482).

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.593C>T	p.Pro198Leu	missense_variant	4/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9 linkuse as main transcript	c.593C>T	p.Pro198Leu	missense_variant	4/16	1	NM_016203.4	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251118

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.000163

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461372

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 21, 2016	We have seen this variant in an individual with LVNC. Testing was done at Invitae. Given the lack of case data we consider this variant to be uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature. The Invitae report notes: The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. The P198L variant was reported online in 1 of 60,507 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/2016). Specifically, the variant was observed in 1 of 5,780 Latino people. A different P198R variant at the same codon was reported online in 7 of 60,507 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/2016). Specifically, the variant was observed in 5 of 4,323 East Asian people and 2 of 33,224 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2017	The P198L variant of uncertain significance in the PRKAG2 gene has not been published in association with PRKAG2-related disorders to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, P198L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, while another missense variant at the same residue (P198A) has been reported in HGMD in association with HCM (Stenson et al., 2014; Alejandra Restrepo-Cordoba et al., 2017), the clinical significance of this variant also remains to be definitively determined. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 29, 2023

This missense variant replaces proline with leucine at codon 198 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PRKAG2-related disorders in the literature. This variant has been identified in 6/282504 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -

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

Fulgent Genetics, Fulgent Genetics

Sep 06, 2021

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 06, 2023

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2022

The p.P198L variant (also known as c.593C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 593. The proline at codon 198 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an autism spectrum disorder cohort that had whole exome sequencing (Jiao J et al. J Mol Neurosci, 2020 Feb;70:219-229). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lethal congenital glycogen storage disease of heart

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 05, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 241096). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This variant is present in population databases (rs41317142, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the PRKAG2 protein (p.Pro198Leu). -

PRKAG2 cardiac syndrome

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 01-04-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

CardioboostCm

Benign

0.0014

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.099

T;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.5

L;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.5

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.15

T;D;D

Sift4G

Benign

0.21

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.30

MVP

0.75

MPC

0.14

ClinPred

0.28

GERP RS

5.3

Varity_R

0.086

gMVP

0.50

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