rs111627309

Positions:

chr7-151564071-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016203.4(PRKAG2):c.1584+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000935 in 1,613,902 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 5 hom. )

Consequence

PRKAG2
NM_016203.4 splice_region, intron

Scores

Splicing: ADA: 0.00002627

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: -1.62

Variant links:

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 links:

PRKAG2 (HGNC:):

PRKAG2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 7-151564071-G-A is Benign according to our data. Variant chr7-151564071-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45699.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=3}. Variant chr7-151564071-G-A is described in Lovd as [Benign]. Variant chr7-151564071-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000953 (145/152168) while in subpopulation SAS AF= 0.00374 (18/4814). AF 95% confidence interval is 0.00242. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 145 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.1584+7C>T		splice_region_variant, intron_variant		ENST00000287878.9	NP_057287.2	Q9UGJ0-1A0A090N8Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9 linkuse as main transcript	c.1584+7C>T		splice_region_variant, intron_variant		1	NM_016203.4	ENSP00000287878.3		Q9UGJ0-1

Frequencies

GnomAD3 genomes

AF:

0.000960

AC:

146

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00374

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00130

AC:

326

AN:

251474

Hom.:

AF XY:

0.00130

AC XY:

177

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00714

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000897

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.000933

AC:

1364

AN:

1461734

Hom.:

Cov.:

AF XY:

0.000949

AC XY:

690

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00230

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000760

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000953

AC:

145

AN:

152168

Hom.:

Cov.:

AF XY:

0.000941

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00374

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00102

EpiCase

AF:

0.000927

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	1584+7C>T in intron 14 of the PRKAG2: This variant is not expected to have clin ical significance because it is not located within the splicing consensus sequen ce. It has been identified in 0.2% (12/7020) of European American chromosomes fr om a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu/EVS; dbSNP rs111627309). 1584+7C>T in intron 14 of the PRKAG2 (rs1116 27309; allele frequency = 0.2%, 12/7020) ** -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PRKAG2: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Wolff-Parkinson-White pattern

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hypertrophic cardiomyopathy 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 17, 2017

- -

Lethal congenital glycogen storage disease of heart

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.14

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000026

dbscSNV1_RF

Benign

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over