7-151876646-G-A

Position:

• chr7-151876646-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016203.4(PRKAG2):​c.-26C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,598,058 control chromosomes in the GnomAD database, including 18,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1807 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16659 hom.)
• Consequence: PRKAG2 NM_016203.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-151876646-G-A is Benign according to our data. Variant chr7-151876646-G-A is described in ClinVar as [Benign]. Clinvar id is 260692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-151876646-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.-26C>T		5_prime_UTR_variant	1/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.-26C>T		5_prime_UTR_variant	1/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22415 AN: 152038 Hom.: 1810 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.176 AC: 42586 AN: 242650 Hom.: 4473 AF XY: 0.171 AC XY: 22578 AN XY: 132338

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.248

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.144 AC: 207749 AN: 1445902 Hom.: 16659 Cov.: 29 AF XY: 0.144 AC XY: 104027 AN XY: 720176

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.147 AC: 22415 AN: 152156 Hom.: 1807 Cov.: 32 AF XY: 0.150 AC XY: 11164 AN XY: 74400

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.137

Alfa AF: 0.130 Hom.: 338

Bravo AF: 0.153

Asia WGS AF: 0.247 AC: 857 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 16115789, 21813245, 20022652) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

Wolff-Parkinson-White pattern Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypertrophic cardiomyopathy 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lethal congenital glycogen storage disease of heart Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs66628686; hg19: chr7-151573731; COSMIC: COSV55222433; COSMIC: COSV55222433;