rs397517269

Variant summary

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

The NM_016203.4(PRKAG2):c.313G>A(p.Val105Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,956 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. V105A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.71

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=0.09233788).

BP6

Variant 7-151781305-C-T is Benign according to our data. Variant chr7-151781305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45714.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000204 (31/152176) while in subpopulation AMR AF= 0.00183 (28/15302). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.313G>A	p.Val105Met	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.313G>A	p.Val105Met	missense_variant	3/16	1	NM_016203.4	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251146

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

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:

0.0000880

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000204

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000741

Hom.:

Bravo

AF:

0.000340

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 27, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Val105Met var iant in PRKAG2 has been identified by our laboratory in 1 individual with HCM an d ventricular tachycardia and 1 individual with HCM/RCM. Both of these individua ls carried a likely pathogenic variant in another gene. This variant has been id entified in 5/66212 European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs397517269). Valine (Val) at positio n 105 is not conserved in mammals or evolutionarily distant species and 2 mammal s (elephant and platypus) carry a methionine (Met) at this position, suggesting that this change may be tolerated. Additional computational prediction tools sug gest that this variant may not impact the protein, though this information is no t predictive enough to rule out pathogenicity. In addition, this variant is loca ted outside the CBS domain region where all pathogenic PRKAG2 variants have been identified(Oliveira 2003). In summary, while the clinical significance of the p .Val105Met variant is uncertain, these data suggest that it is more likely to be benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2023

Identified in a patient with HCM in published literature (Mademont-Soler et al., 2017); this patient harbored additional cardiogenetic variants; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28771489) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2021

The c.313G>A (p.V105M) alteration is located in exon 3 (coding exon 3) of the PRKAG2 gene. This alteration results from a G to A substitution at nucleotide position 313, causing the valine (V) at amino acid position 105 to be replaced by a methionine (M). The alteration is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.313G>A alteration was observed in 0.012% (32/276916) total alleles studied. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.V105 amino acid is somewhat well conserved in available vertebrate species. Both the elephant and the platypus share the proband's methionine as the reference allele at the 105 position. In silico prediction is conflicting:_x000D_ _x000D_ The p.V105M alteration is predicted to be benign by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 25, 2020

- -

Lethal congenital glycogen storage disease of heart

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

CardioboostCm

Benign

0.0058

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.29

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.087

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.083

MetaRNN

Benign

0.092

T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

0.81

L;.

MutationTaster

Benign

0.93

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.25

Sift

Benign

0.082

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.17

B;.

Vest4

0.30

MutPred

0.23

Loss of sheet (P = 0.0181);.;

MVP

0.55

MPC

0.16

ClinPred

0.068

GERP RS

2.9

Varity_R

0.034

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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