chr7-151781320-C-T

Position:

chr7-151781320-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_016203.4(PRKAG2):c.298G>A(p.Gly100Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,613,886 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 173 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18

Conservation

PhyloP100: 2.06

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=0.0072490573).

BP6

Variant 7-151781320-C-T is Benign according to our data. Variant chr7-151781320-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36697.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=9}. Variant chr7-151781320-C-T is described in Lovd as [Benign]. Variant chr7-151781320-C-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.298G>A	p.Gly100Ser	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.298G>A	p.Gly100Ser	missense_variant	3/16	1	NM_016203.4	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

470

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.0359

Gnomad SAS

AF:

0.0342

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00736

AC:

1846

AN:

250804

Hom.:

AF XY:

0.00854

AC XY:

1158

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.000557

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.0318

Gnomad SAS exome

AF:

0.0349

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000891

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00432

AC:

6317

AN:

1461758

Hom.:

173

Cov.:

AF XY:

0.00518

AC XY:

3766

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.0541

Gnomad4 SAS exome

AF:

0.0348

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000492

Gnomad4 OTH exome

AF:

0.00657

GnomAD4 genome

AF:

0.00309

AC:

470

AN:

152128

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

284

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000723

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.0360

Gnomad4 SAS

AF:

0.0343

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00236

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00801

AC:

972

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:18

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 24, 2012	Gly100Ser in exon 3 of PRKAG2: Although this variant changes an amino acid, it i s present at high frequency in Asian populations (2-7%, 1000 Genomes data). This is consistent with its high frequency in Asian probands tested by our laborator y. In addition, this variant is outside of the CBS domain (residues 277-555) wh ere all pathogenic variants in PRKAG2 have so far been identified. In summary, t he variants frequency in the general population suggests that is not disease cau sing in isolation though a modifying effect cannot be ruled out. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2018	Variant summary: PRKAG2 c.298G>A (p.Gly100Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 276670 control chromosomes in the gnomAD database, including 44 homozygotes. The observed variant frequency is approximately 270.79 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.298G>A has been reported in the literature in individuals affected with Cardiomyopathy (Zhang_2013, Zhao_2017), however co-occurrences with other pathogenic variant(s) have been reported (MYBPC3 c.3624delC , p.Lys1209Serfs ; TNNT2 c.274C>T, p.Arg92Trp), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Zhang_2013). Multiple clinical diagnostic laboratories have classified the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2017	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2018	This variant is associated with the following publications: (PMID: 28498465, 28801758, 28138913, 23778007, 27082122, 27153395, 27535533, 27884173, 25637381, 23992123) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PRKAG2: BS1, BS2 -

Wolff-Parkinson-White pattern

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 12, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -

Renal cysts and diabetes syndrome

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Gly100Ser variant in PRKAG2 has been identified in 12 Chinese individuals with Wolff-Parkinson-White syndrome, conduction system disease, and/or hypertrophic cardiomyopathy, segregated with disease in 12 relatives from 1 family (PMID: 23778007), but has also been identified in >3% of South Asian chromosomes and 30 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Functional studies with zebrafish provide some evidence that the p.Gly100Ser variant may slightly impact protein function (PMID: 23992123). However, these types of assays may not accurately represent biological function. This variant is not in the same domain as all other previously identified pathogenic variants, suggesting that this variant may be benign (PMID: 23778007). In summary, this variant meets criteria to be classified as benign for autosomal dominant PRKAG2 cardiac syndrome. -

PRKAG2 cardiac syndrome

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Hypertrophic cardiomyopathy 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 12, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Lethal congenital glycogen storage disease of heart

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.055

T;.

Eigen

Benign

0.036

Eigen_PC

Benign

0.082

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0072

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.82

N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.11

T;D

Sift4G

Benign

0.14

T;T

Polyphen

0.91

P;.

Vest4

0.26

MVP

0.71

MPC

0.14

ClinPred

0.010

GERP RS

4.1

Varity_R

0.12

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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