rs1060503025

chr7-151876589-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016203.4(PRKAG2):c.32A>T(p.Lys11Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K11E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.42

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33943892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.32A>T	p.Lys11Ile	missense_variant	1/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.32A>T	p.Lys11Ile	missense_variant	1/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Oct 18, 2016

p.Lys11Ile (c.32A>T) in the PRKAG2 gene (NM_016203.3) The lab classifies this variant as a variant of unknown significance. Given a lack of case data, we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We do recommend testing for this variant in family members that also have cardiomyopathy. There is no case data. In silico analysis with PolyPhen-2 predicts the variant to be benign. The Lys at codon 11 is weakly conserved across species. No other variants have been reported in association with disease at this codon and nearby codons. This variant falls outside of a known functional domain. There is no variation at codon 11 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 18, 2016). The average coverage at that site in ExAC is 30x. -

Lethal congenital glycogen storage disease of heart Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PRKAG2-related disease. This sequence change replaces lysine with isoleucine at codon 11 of the PRKAG2 protein (p.Lys11Ile). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
CardioboostCm	Uncertain	0.12
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.88	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.033	D
Polyphen		0.97	D
Vest4		0.40
MutPred		0.37		Loss of solvent accessibility (P = 0.0045);
MVP		0.78
MPC		2.1
ClinPred		0.92	D
GERP RS		2.8
Varity_R		0.42
gMVP		0.44

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: rs1060503025; hg19: chr7-151573674;