rs148197254

Variant names:

• chr7-151560609-C-T
• rs148197254
• NM_016203.4:c.1593G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_016203.4(PRKAG2):​c.1593G>A​(p.Arg531Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,613,978 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (32 hom.)
• Consequence: PRKAG2 NM_016203.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 1.61
• Publications: 2 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 7-151560609-C-T is Benign according to our data. Variant chr7-151560609-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00365 (556/152228) while in subpopulation NFE AF = 0.0057 (388/68024). AF 95% confidence interval is 0.00524. There are 0 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 556 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.1593G>A	p.Arg531Arg	synonymous	Exon 15 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.1593G>A	p.Arg531Arg	synonymous	Exon 15 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.1590G>A	p.Arg530Arg	synonymous	Exon 15 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.1593G>A	p.Arg531Arg	synonymous	Exon 15 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.1461G>A	p.Arg487Arg	synonymous	Exon 15 of 16	ENSP00000376549.2	Q9UGJ0-3
	PRKAG2	ENST00000418337.6	TSL:1	c.870G>A	p.Arg290Arg	synonymous	Exon 11 of 12	ENSP00000387386.2	Q9UGJ0-2

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 557 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00349 AC: 878 AN: 251472 AF XY: 0.00347

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00562 AC: 8213 AN: 1461750 Hom.: 32 Cov.: 32 AF XY: 0.00551 AC XY: 4006 AN XY: 727208

African (AFR) AF: 0.00119 AC: 40 AN: 33478

American (AMR) AF: 0.00333 AC: 149 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 183 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86258

European-Finnish (FIN) AF: 0.000824 AC: 44 AN: 53414

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00662 AC: 7365 AN: 1111888

Other (OTH) AF: 0.00596 AC: 360 AN: 60388

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74426

African (AFR) AF: 0.000964 AC: 40 AN: 41512

American (AMR) AF: 0.00445 AC: 68 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00570 AC: 388 AN: 68024

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00509 Hom.: 2

Bravo AF: 0.00405

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00658

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		1.6
Mutation Taster		=98/2	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: rs148197254; hg19: chr7-151257695;