rs2302531

Variant names:

• chr7-151570267-G-A
• rs2302531
• NM_016203.4:c.1052-42C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016203.4(PRKAG2):​c.1052-42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,577,214 control chromosomes in the GnomAD database, including 13,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1123 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12219 hom.)
• Consequence: PRKAG2 NM_016203.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.757
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-151570267-G-A is Benign according to our data. Variant chr7-151570267-G-A is described in ClinVar as Benign. ClinVar VariationId is 260694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

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.1052-42C>T		intron	N/A	NP_057287.2
	PRKAG2	NM_001407021.1		c.1052-42C>T		intron	N/A	NP_001393950.1
	PRKAG2	NM_001407022.1		c.1049-42C>T		intron	N/A	NP_001393951.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.1052-42C>T		intron	N/A	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.920-42C>T		intron	N/A	ENSP00000376549.2
	PRKAG2	ENST00000418337.6	TSL:1	c.329-42C>T		intron	N/A	ENSP00000387386.2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16061 AN: 152046 Hom.: 1119 Cov.: 33

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.148 AC: 36287 AN: 245054 AF XY: 0.149

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.122 AC: 173407 AN: 1425050 Hom.: 12219 Cov.: 29 AF XY: 0.125 AC XY: 88296 AN XY: 708664

African (AFR) AF: 0.0271 AC: 881 AN: 32548

American (AMR) AF: 0.225 AC: 9658 AN: 43008

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4552 AN: 25208

East Asian (EAS) AF: 0.277 AC: 10816 AN: 39074

South Asian (SAS) AF: 0.199 AC: 16813 AN: 84356

European-Finnish (FIN) AF: 0.106 AC: 5465 AN: 51342

Middle Eastern (MID) AF: 0.132 AC: 734 AN: 5564

European-Non Finnish (NFE) AF: 0.108 AC: 117013 AN: 1085316

Other (OTH) AF: 0.127 AC: 7475 AN: 58634

GnomAD4 genome AF: 0.106 AC: 16063 AN: 152164 Hom.: 1123 Cov.: 33 AF XY: 0.109 AC XY: 8113 AN XY: 74374

African (AFR) AF: 0.0307 AC: 1276 AN: 41546

American (AMR) AF: 0.172 AC: 2629 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3472

East Asian (EAS) AF: 0.270 AC: 1395 AN: 5176

South Asian (SAS) AF: 0.213 AC: 1028 AN: 4820

European-Finnish (FIN) AF: 0.106 AC: 1120 AN: 10568

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7663 AN: 67982

Other (OTH) AF: 0.126 AC: 266 AN: 2112

Alfa AF: 0.120 Hom.: 281

Bravo AF: 0.106

Asia WGS AF: 0.252 AC: 878 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		0.76
Mutation Taster		=100/0	polymorphism (auto)

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: rs2302531; hg19: chr7-151267353; COSMIC: COSV55221795; COSMIC: COSV55221795;