Variant rs369687307 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000287878.9(PRKAG2):c.186G>T(p.Lys62Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000103 in 1,458,476 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PRKAG2
ENST00000287878.9 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.36

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG2	NM_016203.4 linkuse as main transcript	c.186G>T	p.Lys62Asn	missense_variant, splice_region_variant	2/16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9 linkuse as main transcript	c.186G>T	p.Lys62Asn	missense_variant, splice_region_variant	2/16	1	NM_016203.4	ENSP00000287878	P3	Q9UGJ0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000814

AC:

AN:

245592

Hom.:

AF XY:

0.00000755

AC XY:

AN XY:

132508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1458476

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000239

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 02, 2010

The Lys62Asn variant has not been reported in the literature. Lysine (Lys) at p osition 62 is conserved in evolutionary distant species, suggesting that a chang e would not be tolerated. In addition, this variant has not been identified in over 1000 Caucasian probands (2000 chromosomes) tested by our laboratory. This l ow frequency increases the likelihood that the variant is pathogenic. However, the Lys62Asn variant is located outside the CBS domain region where all pathogen ic PRKAG2 variants have been identified to date (Oliveira 2003), raising the pos sibility that it is not disease causing in isolation. In summary, additional stu dies are necessary to determine the clinical significance of this variant. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 05, 2024

This missense variant replaces lysine with asparagine at codon 62 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>T nucleotide substitution at the last nucleotide of exon 2 of the PRKAG2 gene, and splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 2/245592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2020

The c.186G>T (p.K62N) alteration is located in exon 2 (coding exon 2) of the PRKAG2 gene. This alteration results from a G to T substitution at nucleotide position 186, causing the lysine (K) at amino acid position 62 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Lethal congenital glycogen storage disease of heart

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 62 of the PRKAG2 protein (p.Lys62Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 45707). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

CardioboostCm

Benign

0.0011

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.086

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.43

N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.069

T;D

Polyphen

0.98

D;.

Vest4

0.53

MutPred

0.36

Loss of methylation at K62 (P = 0.0041);.;

MVP

0.76

MPC

0.34

ClinPred

0.90

GERP RS

5.4

Varity_R

0.37

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.040

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