rs201240745

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The ENST00000287878.9(PRKAG2):c.698C>G(p.Ala233Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,402,108 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. A233E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PRKAG2
ENST00000287878.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: 1.67

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15691051).

BP6

Variant 7-151632125-G-C is Benign according to our data. Variant chr7-151632125-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45733.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=4}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000153 (23/149880) while in subpopulation NFE AF= 0.000313 (21/67024). AF 95% confidence interval is 0.00021. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.698C>G	p.Ala233Gly	missense_variant	5/16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9 linkuse as main transcript	c.698C>G	p.Ala233Gly	missense_variant	5/16	1	NM_016203.4	ENSP00000287878	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.000154

AC:

AN:

149772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000292

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000313

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

160298

Hom.:

AF XY:

0.000217

AC XY:

AN XY:

92082

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000127

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000352

Gnomad NFE exome

AF:

0.000293

Gnomad OTH exome

AF:

0.000280

GnomAD4 exome

AF:

0.000161

AC:

202

AN:

1252228

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

122

AN XY:

621722

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000101

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000154

Gnomad4 NFE exome

AF:

0.000186

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.000153

AC:

AN:

149880

Hom.:

Cov.:

AF XY:

0.000137

AC XY:

AN XY:

73136

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000292

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000103

Gnomad4 NFE

AF:

0.000313

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000147

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2017	Variant summary: The PRKAG2 c.698C>G (p.Ala233Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 17/77136 control chromosomes, predominantly observed in the European subpopulation at a frequency of 0.000371 (17/45836). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic PRKAG2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of European origin. One clinical diagnostic laboratory identified this variant in one infant with unspecified cardiomyopathy and classified this variant as uncertain significance without additional evidence for independent review. One reputable database classified this variant as "unlikely to be pathogenic". Taken together, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PRKAG2: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2024	Identified in a infant with hypoplastic left heart syndrome (HLHS) and left ventricular noncompaction (LVNC) and in a patient with HCM (PMID: 31527676, 35626289); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31527676, 35626289) -

Cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 12, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 14, 2012

Variant classified as Uncertain Significance - Favor Benign. The Ala233Gly varia nt in PRKAG2 has not been reported in the literature, but has been identified in one infant with unspecified cardiomyopathy previously tested by our laboratory. This variant is located outside of the CBS domain, where all pathogenic PRKAG2 mutations have been identified to date (Oliveira 2003), raising the possibility that it may be tolerated. Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Ala233G ly variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Ala233Gly variant. -

Wolff-Parkinson-White pattern

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. -

Hypertrophic cardiomyopathy 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2023

The p.A233G variant (also known as c.698C>G), located in coding exon 5 of the PRKAG2 gene, results from a C to G substitution at nucleotide position 698. The alanine at codon 233 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in an acute heart failure in infancy cohort; however, clinical details were limited (Ritter A et al. Genet Med, 2020 Feb;22:423-426). This amino acid position is well 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. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Nov 18, 2019

- -

Lethal congenital glycogen storage disease of heart

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

CardioboostCm

Benign

0.021

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Benign

0.083

T;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.72

T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.37

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.30

MutPred

0.35

Gain of catalytic residue at A233 (P = 0.0438);.;.;

MVP

0.67

MPC

0.63

ClinPred

0.027

GERP RS

2.5

Varity_R

0.085

gMVP

0.45

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