rs397517277

chr7-151675484-G-C

Variant summary

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

The NM_016203.4(PRKAG2):c.620C>G(p.Ser207Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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:6
• Conservation: PhyloP100: 6.24

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=0.35241383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.620C>G	p.Ser207Cys	missense_variant	4/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.620C>G	p.Ser207Cys	missense_variant	4/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal congenital glycogen storage disease of heart Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2021	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. 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. ClinVar contains an entry for this variant (Variation ID: 45729). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257, 32746448). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the PRKAG2 protein (p.Ser207Cys). -

Wolff-Parkinson-White pattern Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 06, 2012

Variant classified as Uncertain Significance - Favor Benign. The Ser207Cys varia nt in PRKAG2 has not been reported in the literature nor previously identified i n >1500 Caucasian probands tested by our laboratory. In addition, this variant h as not been identified in large and broad populations by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to establish this with confidence. Computational analyses (biochemical amino acid properties, conservation, AlignG VGD, PolyPhen2, and SIFT) suggest that the Ser207Cys variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. In addition, the variant is located outside the CBS domain of the PRKAG2 pr otein that contains all pathogenic PRKAG2 variants have been identified to date. Additional information is needed to fully assess the clinical significance of the Ser207Cys variant. -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Wolff-Parkinson-White pattern;C1833236:Hypertrophic cardiomyopathy 6;C1849813:Lethal congenital glycogen storage disease of heart Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
CardioboostCm	Benign	0.00098
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.10	T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.42	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.027	D;D;D
Sift4G	Uncertain	0.053	T;T;T
Polyphen		0.89	P;.;.
Vest4		0.34
MutPred		0.32		Loss of phosphorylation at S207 (P = 0.0513);.;.;
MVP		0.54
MPC		0.37
ClinPred		0.77	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.26

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: rs397517277; hg19: chr7-151372570;