7-151632125-G-C

Variant names:

• chr7-151632125-G-C
• rs201240745
• NM_016203.4:c.698C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001407021.1(PRKAG2):​c.698C>G​(p.Ala233Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,402,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A233S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PRKAG2 NM_001407021.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 1.67
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15691051).
• BP6: Variant 7-151632125-G-C is Benign according to our data. Variant chr7-151632125-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45733.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000153 (23/149880) while in subpopulation NFE AF = 0.000313 (21/67024). AF 95% confidence interval is 0.00021. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407021.1. 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.698C>G	p.Ala233Gly	missense	Exon 5 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.698C>G	p.Ala233Gly	missense	Exon 5 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.698C>G	p.Ala233Gly	missense	Exon 5 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.698C>G	p.Ala233Gly	missense	Exon 5 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.566C>G	p.Ala189Gly	missense	Exon 5 of 16	ENSP00000376549.2
	PRKAG2	ENST00000418337.6	TSL:1	c.-26C>G		5_prime_UTR	Exon 1 of 12	ENSP00000387386.2

Frequencies

GnomAD3 genomes AF: 0.000154 AC: 23 AN: 149772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000313

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 28 AN: 160298 AF XY: 0.000217

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000127

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000352

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.000280

GnomAD4 exome AF: 0.000161 AC: 202 AN: 1252228 Hom.: 0 Cov.: 30 AF XY: 0.000196 AC XY: 122 AN XY: 621722

African (AFR) AF: 0.00 AC: 0 AN: 26060

American (AMR) AF: 0.00 AC: 0 AN: 31632

Ashkenazi Jewish (ASJ) AF: 0.000101 AC: 2 AN: 19742

East Asian (EAS) AF: 0.00 AC: 0 AN: 26508

South Asian (SAS) AF: 0.00 AC: 0 AN: 65680

European-Finnish (FIN) AF: 0.000154 AC: 5 AN: 32572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4484

European-Non Finnish (NFE) AF: 0.000186 AC: 185 AN: 997298

Other (OTH) AF: 0.000207 AC: 10 AN: 48252

GnomAD4 genome AF: 0.000153 AC: 23 AN: 149880 Hom.: 0 Cov.: 32 AF XY: 0.000137 AC XY: 10 AN XY: 73136

African (AFR) AF: 0.00 AC: 0 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

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

European-Finnish (FIN) AF: 0.000103 AC: 1 AN: 9748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000313 AC: 21 AN: 67024

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000364 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.000147 AC: 17

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
CardioboostCm	Benign	0.021
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.25
Sift	Benign	0.55	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.35		Gain of catalytic residue at A233 (P = 0.0438)
MVP		0.67
MPC		0.63
ClinPred		0.027	T
GERP RS		2.5
PromoterAI		-0.15	Neutral
Varity_R		0.085
gMVP		0.45
Mutation Taster		=86/14	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: rs201240745; hg19: chr7-151329211;