rs397517264

Variant names:

• chr7-151565729-C-T
• rs397517264
• NM_016203.4:c.1390G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BS1_Supporting BS2

The NM_016203.4(PRKAG2):​c.1390G>A​(p.Asp464Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000356 (52/1461478) while in subpopulation MID AF= 0.00173 (10/5768). AF 95% confidence interval is 0.00094. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.1390G>A	p.Asp464Asn	missense_variant	Exon 12 of 16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1390G>A	p.Asp464Asn	missense_variant	Exon 12 of 16	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251482 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461478 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727064

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 6 Uncertain:3

Jun 17, 2020

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Oct 29, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This variant has been identified as part of our research program. The variant was identified in 1 HCM proband of Lebanese descent who was tested at Blueprint Genetics. For further information please feel free to contact us. -

not specified Uncertain:2

May 23, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Asp464Asn (c. 1390 G>A) in PRKAG2 This variant is novel. This results in a non-conservative amino acid change, where a negatively-charged amino acid (Aspartic Acid) is changed to a neutral, polar amino acid (Asparagine). This variant is predicted to be benign by PolyPhen-2 analysis. This residue is conserved across species. No other disease-causing variants have been reported at this or nearby codons. The variant was not observed in 313 individuals of various ethnic backgrounds at GeneDx. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,000 Caucasian and African American individuals (as of May 2012). The variant is not listed in dbSNP or 1000 genomes (as of May 2012). -

Jun 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp464Asn variant in PRKAG2 has been identified by our laboratory in 1 Lebanese individua l with LVNC and WPW and segregated with disease in 1 affected relative. This var iant has been identified in 5/66738 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517264). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In addition, this variant is located wit hin the CBS domain region where all pathogenic PRKAG2 variants have been identif ied to date (Oliveira 2003). In summary, while there is some suspicion for a pat hogenic role, the clinical significance of the p.Asp464Asn variant is uncertain. -

Cardiomyopathy Uncertain:2

Nov 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 464 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (ClinVar: SCV001156311.1, SCV001468149.1, SCV000264153.2) or dilated cardiomyopathy (PMID: 33029862). This variant has also been reported in two related individuals affected with left ventricular noncompaction cardiomyopathy and Wolff-Parkinson-White syndrome (ClinVar: SCV000062594.5). This variant has been identified in 8/251482 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. -

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Aug 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PRKAG2 c.1390G>A; p.Asp464Asn variant (rs397517264, ClinVar Variation ID: 45697) is reported in the literature in two individuals affected with dilated cardiomyopathy (DCM) and one individual affected with primary electrical disease (Perret 2024, Proost 2017, VanDyke 2021). This variant is found in the non-Finnish European population with an allele frequency of 0.007% (8/113758 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.506). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Perret C et al. DNA-pools targeted-sequencing as a robust cost-effective method to detect rare variants: Application to dilated cardiomyopathy genetic diagnosis. Clin Genet. 2024 Feb;105(2):185-189. PMID: 37904629. Proost D et al. Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. J Mol Diagn. 2017 May;19(3):445-459. PMID: 28341588. VanDyke RE et al. Impact of variant reclassification in the clinical setting of cardiovascular genetics. J Genet Couns. 2021 Apr;30(2):503-512. PMID: 33029862. -

Jul 10, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in ClinVar as a variant of uncertain significance by several laboratories; one laboratory identified this variant in 1 Lebanese individual with LVNC and Wolff-Parkinson-White syndrome, and the variant segregated with disease in 1 affected relative (SCV000062594.4; ClinVar Variant ID# 45697; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28341588) -

Wolff-Parkinson-White pattern Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Jul 23, 2015

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1

Apr 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 464 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (ClinVar: SCV001156311.1, SCV001468149.1, SCV000264153.2) or dilated cardiomyopathy (PMID: 33029862). This variant has also been reported in two related individuals affected with left ventricular noncompaction cardiomyopathy and Wolff-Parkinson-White syndrome (ClinVar: SCV000062594.5). This variant has been identified in 8/251482 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

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D464N variant (also known as c.1390G>A), located in coding exon 12 of the PRKAG2 gene, results from a G to A substitution at nucleotide position 1390. The aspartic acid at codon 464 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in one individual from a primary electrical disease cohort, who had additional cardiac variants also reported (Proost D et al. J Mol Diagn, 2017 05;19:445-459). This alteration has also been reported in association with dilated cardiomyopathy (DCM) (VanDyke RE et al. J Genet Couns, 2021 Apr;30:503-512; Perret C et al. Clin Genet, 2024 Feb;105:185-189). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lethal congenital glycogen storage disease of heart Uncertain:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 464 of the PRKAG2 protein (p.Asp464Asn). This variant is present in population databases (rs397517264, gnomAD 0.007%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy and/or dilated cardiomyopathy (PMID: 33029862; internal data). ClinVar contains an entry for this variant (Variation ID: 45697). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRKAG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Benign	0.096
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N;D;N
REVEL	Uncertain	0.51
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.17	B;.;.;.
Vest4		0.89
MutPred		0.69		Gain of sheet (P = 0.0827);.;.;.;
MVP		0.86
MPC		0.96
ClinPred		0.33	T
GERP RS		6.1
Varity_R		0.14
gMVP		0.87

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

Other links and lift over

dbSNP: rs397517264; hg19: chr7-151262815;