NM_016203.4:c.352C>T

Variant names:

• chr7-151781266-G-A
• rs1554596200
• NM_016203.4:c.352C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016203.4(PRKAG2):​c.352C>T​(p.Pro118Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,796 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• PRKAG2-related cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• lethal congenital glycogen storage disease of heart

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Wolff-Parkinson-White syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29568756).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016203.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.352C>T	p.Pro118Ser	missense	Exon 3 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.352C>T	p.Pro118Ser	missense	Exon 3 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.352C>T	p.Pro118Ser	missense	Exon 3 of 15	NP_001393951.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.352C>T	p.Pro118Ser	missense	Exon 3 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.220C>T	p.Pro74Ser	missense	Exon 3 of 16	ENSP00000376549.2
	PRKAG2	ENST00000488258.5	TSL:1	n.352C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000420783.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PRKAG2-related cardiomyopathy Uncertain:1

Apr 07, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as VUS-3B. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 1 heterozygote(s), 0 homozygote(s)) . Additional information: Variant is predicted to result in a missense amino acid change from proline to serine; This variant is non-coding in an alternative transcript. It is intronic or non-coding in multiple other RefSeq trancripts, including NM_024429, which has the highest overall expression level in human tissue and NM_001304527, which has a higher expression level in heart tissue (GTEx). In addition, other pathogenic/likely pathogenic variants have not been reported in this exon (ClinVar); This variant is heterozygous; This gene is associated with autosomal dominant disease; Previous evidence of pathogenicity for this variant is inconclusive. It has been classified as a variant of uncertain significance by two clinical laboratories (ClinVar); No published segregation evidence has been identified for this variant; No published functional evidence has been identified for this variant; No comparable missense variants have previous evidence for pathogenicity; Variant is not located in an established domain, motif, hotspot or informative constraint region; Missense variant with inconclusive in silico prediction and uninformative conservation; Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 6 (MIM#600858), lethal congenital glycogen storage disease of heart (MIM#261740) and Wolff-Parkinson-White syndrome (MIM#194200); Variants in this gene are known to have variable expressivity. Intrafamilial and interfamilial variable expressivity have been reported (PMIDs: 11407343, 28431061); Inheritance information for this variant is not currently available in this individual.

Hypertrophic cardiomyopathy Uncertain:1

Jun 26, 2023

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 proline with serine at codon 118 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 PRKAG2-related disorders in the literature. This variant has not been identified 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.

Lethal congenital glycogen storage disease of heart Uncertain:1

Mar 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 533883). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PRKAG2 protein function. 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. This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 118 of the PRKAG2 protein (p.Pro118Ser). This variant is not present in population databases (gnomAD no frequency).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Benign	0.0032
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.36	T
Polyphen		0.80	P
Vest4		0.35
MutPred		0.31		Gain of phosphorylation at P118 (P = 3e-04)
MVP		0.83
MPC		0.29
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.17
gMVP		0.38
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554596200; hg19: chr7-151478352;