rs142808871

chr7-151781262-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016203.4(PRKAG2):c.356G>A(p.Arg119Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R119G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 5.36

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23307097).
• BS2: High AC in GnomAdExome at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.356G>A	p.Arg119Gln	missense_variant	3/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.356G>A	p.Arg119Gln	missense_variant	3/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000876 AC: 22 AN: 251234 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135778

Gnomad AFR exome AF: 0.00

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: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461778 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727170

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74418

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2012	This missense change is denoted p.Arg119Gln (R119Q) at the protein level, and c.356 G>A at the cDNA level. The Arg119Gln variant in the PRKAG2 gene also has not been published as a disease-causing mutation or benign polymorphism. Arg119Gln results in a semi-conservative amino acid substitution of a positively-charged Arginine with a neutral Glutamine residue. No mutations in surrounding residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. The NHLBI ESP Exome Variant Server reports Arg119Gln was present in 1 out of 7019 alleles from individuals of European ancestry; however, this variant was not observed in up to 200 alleles from control individuals of Caucasian ancestry tested at GeneDx. Collectively, these findings indicate that Arg119Gln is not a common variant in this population. In summary, we cannot unequivocally determine whether Arg119Gln in the PRKAG2 gene is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s). -

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 04, 2012	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.Arg119Gln (R119Q; c.356G>A, exon 3) in the PRKAG2 As of December 28, 2011, no variation at codon 119 of PRKAG2 has been reported in the literature (according to searches of PubMed and Google). However, it is present as a rare variant in the NHLBI Exome Sequencing Project data set. This is a non-conservative [NOTE: semi-conservative??] amino acid substitution in which a basic, positively-charged Arginine is replaced by a neutral, polar Glutamine with a shorter sidechain. The change is at an Arginine residue that is highly conserved across 35 vertebrates, although it is a Histidine in Zebrafish. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. Of note, the variant was reported in the NHLBI Exome Sequencing Project data set (http://evs.gs.washington.edu/EVS/) in 1 of 3509 Caucasian individuals and 0 of 1869 African-American individuals. The phenotype of these individuals is not publicly available, however the cohort has been screened to exclude individuals with evidence of Mendelian cardiac disease. The variant is reported in dbSNP (www.ncbi.nlm.nih.gov/SNP) as rs142808871, but this appears to refer to the NHLBI data. GeneDx reports that the variant was absent in up to 100 presumably healthy individuals of Caucasian ancestry. It is not reported in 1000 Genomes (http://browser.1000genomes.org/index.html), which contains 1092 individuals as of December 28, 2011—over 400 of them of European ancestry. In total, therefore, the variant has been seen in 1 out of over 6500 multiethnic, non-clinically-ascertained individuals (nearly 4000 of them Caucasian like the patient). -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 11, 2010	Variant classified as Uncertain Significance - Favor Benign. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 29, 2023

This missense variant replaces arginine with glutamine at codon 119 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: 35026164). This variant has been identified in 22/251234 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. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 28, 2023

This missense variant replaces arginine with glutamine at codon 119 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 22/251234 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

Feb 09, 2016

The c.356G>A (p.R119Q) 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 356, causing the arginine (R) at amino acid position 119 to be replaced by a glutamine (Q). 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

Oct 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
CardioboostCm	Benign	0.067
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.32	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.49	T;T
Polyphen		1.0	D;.
Vest4		0.53
MVP		0.74
MPC		0.51
ClinPred		0.34	T
GERP RS		5.1
Varity_R		0.22
gMVP		0.32

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: rs142808871; hg19: chr7-151478348; COSMIC: COSV55236567;