rs148791216

Positions:

chr7-151781371-G-A

Variant summary

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

The NM_016203.4(PRKAG2):c.247C>T(p.Pro83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,136 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. P83L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 3 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14

Conservation

PhyloP100: 0.917

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:

PRKAG2 (HGNC:):

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=0.013887823).

BP6

Variant 7-151781371-G-A is Benign according to our data. Variant chr7-151781371-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45711.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=2, Benign=1}. Variant chr7-151781371-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000361 (55/152310) while in subpopulation AMR AF= 0.000915 (14/15304). AF 95% confidence interval is 0.000552. 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 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.247C>T	p.Pro83Ser	missense_variant	3/16	ENST00000287878.9	NP_057287.2	Q9UGJ0-1A0A090N8Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9 linkuse as main transcript	c.247C>T	p.Pro83Ser	missense_variant	3/16	1	NM_016203.4	ENSP00000287878.3		Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000449

AC:

110

AN:

244752

Hom.:

AF XY:

0.000495

AC XY:

AN XY:

133240

show subpopulations

Gnomad AFR exome

AF:

0.000199

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.000707

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000511

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000324

AC:

473

AN:

1460826

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

272

AN XY:

726666

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000258

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000361

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000621

Hom.:

Bravo

AF:

0.000506

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000461

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 28, 2015	p.Pro83Ser in exon 3 of PRKAG2: This variant has been reported in an HCM patient who carried a second, pathogenic HCM variant (Scheffold 2011). It is not expect ed to have clinical significance because it has been identified in various large populations including 0.14% (22/15396) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148791216) and is located outside the CBS domain region (residues 277-555) where all patho genic PRKAG2 variants have been identified to date. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Oct 28, 2019	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2018	- -

Wolff-Parkinson-White pattern

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 16, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hypertrophic cardiomyopathy 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 16, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Heart failure

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Mar 14, 2017

- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2019

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

CardioboostCm

Benign

0.0015

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.047

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.20

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.16

Sift

Benign

0.70

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;.

Vest4

0.13

MVP

0.46

MPC

0.14

ClinPred

0.0022

GERP RS

1.6

Varity_R

0.028

gMVP

0.12

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