rs182750960

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_016203.4(PRKAG2):c.206C>T(p.Pro69Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,608,054 control chromosomes in the GnomAD database, including 1 homozygotes. 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. P69R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

PRKAG2
NM_016203.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 7.11

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13425148).

BS2

High AC in GnomAdExome at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.206C>T	p.Pro69Leu	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.206C>T	p.Pro69Leu	missense_variant	3/16	1	NM_016203.4	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

233582

Hom.:

AF XY:

0.0000550

AC XY:

AN XY:

127310

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000903

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000568

Gnomad SAS exome

AF:

0.000100

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000581

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1455890

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

723904

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000684

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000700

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000568

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000743

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 23, 2023	This missense variant replaces proline with leucine at codon 69 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25611685). This variant has been identified in 15/264942 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 18, 2020	The PRKAG2 c.206C>T; p.Pro69Leu variant (rs182750960), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 45708). This variant is found in the general population with an overall allele frequency of 0.01% (15/264942 alleles) in the Genome Aggregation Database. The proline at codon 69 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.199). Due to limited information, the clinical significance of the p.Pro69Leu variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2016	The P69L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P69L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P69L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 03, 2012

Variant classified as Uncertain Significance - Favor Benign. The Pro69Leu varian t (PRKAG2) has not been reported in the literature nor previously identified by our laboratory, but is listed in dbSNP (rs182750960) without frequency informati on. Proline (Pro) at position 69 is not conserved in mammals, and computational analyses (AlignGVGD, PolyPhen2, and SIFT) suggest that the Pro69Leu variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Although this data supports that the Pro69Leu variant may be benign, additional studies are needed to fully assess its clinical significance . -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 10, 2023

This missense variant replaces proline with leucine at codon 69 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25611685). This variant has been identified in 15/264942 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.206C>T (p.P69L) alteration is located in exon 3 (coding exon 3) of the PRKAG2 gene. This alteration results from a C to T substitution at nucleotide position 206, causing the proline (P) at amino acid position 69 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Lethal congenital glycogen storage disease of heart

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

CardioboostCm

Benign

0.0012

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.051

T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.92

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.27

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.045

D;T

Polyphen

0.0

B;.

Vest4

0.17

MVP

0.39

MPC

0.14

ClinPred

0.093

GERP RS

4.1

Varity_R

0.050

gMVP

0.15

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