NM_016203.4:c.826A>G

Variant names:

• chr7-151595383-T-C
• rs727505340
• NM_016203.4:c.826A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_016203.4(PRKAG2):​c.826A>G​(p.Thr276Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.68
• Publications: 3 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 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, 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: Genomics England PanelApp
• Wolff-Parkinson-White syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000274 (4/1461652) while in subpopulation SAS AF = 0.0000464 (4/86256). AF 95% confidence interval is 0.0000158. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.826A>G	p.Thr276Ala	missense	Exon 6 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.826A>G	p.Thr276Ala	missense	Exon 6 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.823A>G	p.Thr275Ala	missense	Exon 6 of 15	NP_001393951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.826A>G	p.Thr276Ala	missense	Exon 6 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.694A>G	p.Thr232Ala	missense	Exon 6 of 16	ENSP00000376549.2	Q9UGJ0-3
	PRKAG2	ENST00000418337.6	TSL:1	c.103A>G	p.Thr35Ala	missense	Exon 2 of 12	ENSP00000387386.2	Q9UGJ0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251390 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461652 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
CardioboostCm	Benign	0.0072
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.12	B
Vest4		0.77
MutPred		0.38		Gain of ubiquitination at K279 (P = 0.0882)
MVP		0.94
MPC		0.67
ClinPred		0.96	D
GERP RS		3.7
Varity_R		0.48
gMVP		0.59
Mutation Taster		=45/55	disease causing

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: rs727505340; hg19: chr7-151292469;