rs139579816

Positions:

chr7-151781293-A-C

Variant summary

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

The NM_016203.4(PRKAG2):c.325T>G(p.Ser109Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 3.78

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=0.033177406).

BP6

Variant 7-151781293-A-C is Benign according to our data. Variant chr7-151781293-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45715.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr7-151781293-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000263 (40/152280) while in subpopulation AFR AF= 0.000963 (40/41542). AF 95% confidence interval is 0.000726. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.325T>G	p.Ser109Ala	missense_variant	3/16	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.325T>G	p.Ser109Ala	missense_variant	3/16	1	NM_016203.4	ENSP00000287878	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251200

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.000925

Gnomad AMR exome

AF:

0.0000289

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:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000263

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000768

Hom.:

Bravo

AF:

0.000340

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2016	Variant summary: The PRKAG2 c.325T>G (p.Ser109Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant is located outside the CBS domain region where pathogenic PRKAG2 variants have been known to cluster (InterPro, Oliveira 2003), reducing the likelihood that it is disease causing. This variant was found in 8/120812 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0007761 (8/10308). This frequency is about 31 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 African origin. This variant has been found in multiple patients with cardiomyopathy from published (Kindel_2012) as well as unpublished (LMM-PH) sources. The variant did not cosegregate with disease in a family (LMM-PH). Two clinical diagnostic laboratories have classified this variant as uncertain significance. Taken together, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 13, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ser109Ala var iant in PRKAG2 has been identified in 8/10308 of African chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs139579816). Th is variant has been identified by our laboratory in 3 individuals (1 Black infan t with HCM, 1 Black teenager with RCM/LVNC, and 1 adult of unspecified ethnicity with DCM); however, it was not present in an affected sibling of the infant wit h HCM and was identified in the unaffected mother, both of whom carried another variant of unknown significance in another gene. This variant is located outside the CBS domain region where all pathogenic PRKAG2 variants have been identified to date (Oliveira 2003), reducing the likelihood that it is disease causing. Co mputational prediction tools and conservation analysis also suggest that it may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ser109A la variant is uncertain, these data suggest that it is more likely to be benign. -

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

PRKAG2 NM_016203.3 exon 3 p.Ser109Ala (c.325T>G): This variant has been reported in the literature in at least one individual with HCM (Kindel 2012 PMID:22555271). This variant is also present in 0.08% (22/24932) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-151478379-A-C) and is present in ClinVar (Variation ID:45715). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 27, 2021

- -

Lethal congenital glycogen storage disease of heart

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

CardioboostCm

Benign

0.0029

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.55

N;.

MutationTaster

Benign

0.92

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.070

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.92

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.089

B;.

Vest4

0.31

MVP

0.68

MPC

0.13

ClinPred

0.066

GERP RS

4.0

Varity_R

0.055

gMVP

0.087

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