rs77902041

Variant names:

• chr7-151876495-G-A
• rs77902041
• NM_016203.4:c.114+12C>T

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.114+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 1,601,166 control chromosomes in the GnomAD database, including 3,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (263 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3689 hom.)
• Consequence: PRKAG2 NM_016203.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.395

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=-0.71).
• BP6: Variant 7-151876495-G-A is Benign according to our data. Variant chr7-151876495-G-A is described in ClinVar as [Benign]. Clinvar id is 45689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-151876495-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.114+12C>T		intron_variant	Intron 1 of 15	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.114+12C>T		intron_variant	Intron 1 of 15	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7416 AN: 152146 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0760

Gnomad OTH AF: 0.0469

GnomAD3 exomes AF: 0.0509 AC: 12390 AN: 243254 Hom.: 405 AF XY: 0.0523 AC XY: 6932 AN XY: 132464

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.0324

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0323

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.0736

Gnomad OTH exome AF: 0.0610

GnomAD4 exome AF: 0.0687 AC: 99576 AN: 1448904 Hom.: 3689 Cov.: 31 AF XY: 0.0677 AC XY: 48837 AN XY: 721456

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.0354

Gnomad4 ASJ exome AF: 0.0650

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0333

Gnomad4 FIN exome AF: 0.0570

Gnomad4 NFE exome AF: 0.0779

Gnomad4 OTH exome AF: 0.0637

GnomAD4 genome AF: 0.0487 AC: 7418 AN: 152262 Hom.: 263 Cov.: 32 AF XY: 0.0465 AC XY: 3460 AN XY: 74456

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0333

Gnomad4 ASJ AF: 0.0649

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0325

Gnomad4 FIN AF: 0.0515

Gnomad4 NFE AF: 0.0760

Gnomad4 OTH AF: 0.0459

Alfa AF: 0.0673 Hom.: 63

Bravo AF: 0.0466

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

114+12C>T variant in Intron 1 of PRKAG2: This variant is not expected to have cl inical significance because it has been identified in 8% (533/6487) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs77902041) . -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 27, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 14, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Wolff-Parkinson-White pattern Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Benign:1

Sep 29, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 08, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Lethal congenital glycogen storage disease of heart Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.95

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: rs77902041; hg19: chr7-151573580;