rs397517277

Variant names:

• chr7-151675484-G-C
• rs397517277
• NM_016203.4:c.620C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/23 in silico tools predict 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. S207P) has been classified 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
• Publications: 1 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=0.35241383).

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.620C>G	p.Ser207Cys	missense	Exon 4 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.620C>G	p.Ser207Cys	missense	Exon 4 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.620C>G	p.Ser207Cys	missense	Exon 4 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.620C>G	p.Ser207Cys	missense	Exon 4 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.488C>G	p.Ser163Cys	missense	Exon 4 of 16	ENSP00000376549.2
	PRKAG2	ENST00000488258.5	TSL:1	n.620C>G		non_coding_transcript_exon	Exon 4 of 10	ENSP00000420783.1

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

African (AFR) AF: 0.0000299 AC: 1 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: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Lethal congenital glycogen storage disease of heart (2)
-	1	-	Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)
-	1	-	not specified (1)
-	1	-	Wolff-Parkinson-White pattern (1)
-	1	-	Wolff-Parkinson-White pattern;C1833236:Hypertrophic cardiomyopathy 6;C1849813:Lethal congenital glycogen storage disease of heart (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	1.4	L
PhyloP100		6.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.053	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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs397517277; hg19: chr7-151372570;