rs121908988

chr7-151568801-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_016203.4(PRKAG2):c.1148A>G(p.His383Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H383Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.81

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain CBS 2 (size 58) in uniprot entity AAKG2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_016203.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 7-151568801-T-C is Pathogenic according to our data. Variant chr7-151568801-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6847.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.1148A>G	p.His383Arg	missense_variant	11/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1148A>G	p.His383Arg	missense_variant	11/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2001

- -

Lethal congenital glycogen storage disease of heart Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 16, 2023

Experimental studies have shown that this missense change affects PRKAG2 function (PMID: 14722619). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 383 of the PRKAG2 protein (p.His383Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PRKAG2-related conditions (PMID: 11371514, 32646569; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as His142Arg. ClinVar contains an entry for this variant (Variation ID: 6847). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRKAG2 protein function. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 15, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The p.His383Arg variant in PRKAG2 has been reported in 1 individual with HCM and conduction abn ormalities, segregated with disease in 2 affected relatives (Blair 2001), and wa s absent from large population studies. In vitro functional studies provide some evidence that the p.His383Arg variant may impact protein function (Scott 2004). However, these types of assays may not accurately represent biological function . Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while there is so me suspicion for a pathogenic role, the clinical significance of the p.His383Arg variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2023

Not observed in large population cohorts (gnomAD); Published in vitro functional study suggests this variant may affect protein function (Scott et al., 2004), although it is unclear how these studies may translate to a pathogenic role in vivo; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28431061, 17667862, 15877279, 11748095, 32646569, 32259713, 11371514, 14722619) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	1.7	L;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Benign	0.21	T;D;T;T;D
Sift4G	Pathogenic	0.0	D;T;D;D;D
Polyphen		0.96	D;.;.;.;.
Vest4		0.94
MutPred		0.87		Gain of MoRF binding (P = 0.0408);.;.;.;.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.98

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: rs121908988; hg19: chr7-151265887;