rs397517264

Variant names:

• chr7-151565729-C-T
• rs397517264
• NM_016203.4:c.1390G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BS1_Supporting BS2

The NM_016203.4(PRKAG2):​c.1390G>A​(p.Asp464Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D464E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:14
• Conservation: PhyloP100: 7.62
• 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000356 (52/1461478) while in subpopulation MID AF = 0.00173 (10/5768). AF 95% confidence interval is 0.00094. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 52 AD gene.

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.1390G>A	p.Asp464Asn	missense	Exon 12 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.1390G>A	p.Asp464Asn	missense	Exon 12 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.1387G>A	p.Asp463Asn	missense	Exon 12 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.1390G>A	p.Asp464Asn	missense	Exon 12 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.1258G>A	p.Asp420Asn	missense	Exon 12 of 16	ENSP00000376549.2	Q9UGJ0-3
	PRKAG2	ENST00000418337.6	TSL:1	c.667G>A	p.Asp223Asn	missense	Exon 8 of 12	ENSP00000387386.2	Q9UGJ0-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251482 AF XY: 0.0000368

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: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461478 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727064

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111646

Other (OTH) AF: 0.0000497 AC: 3 AN: 60372

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000832 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hypertrophic cardiomyopathy 6 (3)
-	2	-	Cardiomyopathy (2)
-	2	-	not provided (2)
-	2	-	not specified (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Lethal congenital glycogen storage disease of heart (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)
-	1	-	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostCm	Benign	0.096
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.51
Sift	Benign	0.18	T
Sift4G	Benign	0.28	T
Polyphen		0.17	B
Vest4		0.89
MutPred		0.69		Gain of sheet (P = 0.0827)
MVP		0.86
MPC		0.96
ClinPred		0.33	T
GERP RS		6.1
Varity_R		0.14
gMVP		0.87
Mutation Taster		=54/46	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: rs397517264; hg19: chr7-151262815;