rs201878539

Variant names:

Variant summary

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

The NM_016203.4(PRKAG2):c.1318C>T(p.His440Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000962 in 1,611,996 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).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 4.61

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=0.026747912).

BP6

Variant 7-151565801-G-A is Benign according to our data. Variant chr7-151565801-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45696.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000486 (74/152320) while in subpopulation AFR AF= 0.00161 (67/41562). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4 link	c.1318C>T	p.His440Tyr	missense_variant	Exon 12 of 16	ENST00000287878.9	NP_057287.2	Q9UGJ0-1A0A090N8Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9 link	c.1318C>T	p.His440Tyr	missense_variant	Exon 12 of 16	1	NM_016203.4	ENSP00000287878.3		Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000478

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251470

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000555

AC:

AN:

1459676

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

726244

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000486

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.000392

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:

0.000473

Alfa

AF:

0.000109

Hom.:

Bravo

AF:

0.000665

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

May 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.His440Tyr in exon 12 of PRKAG2: This variant is not expected to have clinical significance due to its frequency in the general population and lack of evolutio nary conservation of the affected amino acid. It has been identified in 0.2% (20 /10406) of African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs201878539) and 3 mammals (guinea pig, rabbit, and aardvark) have a tyrosine (Tyr) at this position despite high nearby amino a cid conservation, suggesting that this change may be tolerated. -

Dec 15, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 11, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PRKAG2 c.1318C>T (p.His440Tyr) results in a conservative amino acid change located in the CBS domain (IPR000644) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 282880 control chromosomes, predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 68 fold the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1318C>T has been reported in the literature in an individual affected with dilated Cardiomyopathy (Pugh_2014). This report however, does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Uncertain:1Benign:1

Dec 29, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PRKAG2-related disorder

Benign:1

Jan 27, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiomyopathy

Benign:1

Dec 06, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal congenital glycogen storage disease of heart

Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 13, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

CardioboostCm

Benign

0.0099

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.37

T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.56

N;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.63

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.32

MVP

0.58

MPC

0.73

ClinPred

0.019

GERP RS

4.3

Varity_R

0.13

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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