rs369687307

chr7-151786470-C-Achr7-151786470-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_016203.4(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. 2/2 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 NM_016203.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.36

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000814 AC: 2 AN: 245592 Hom.: 0 AF XY: 0.00000755 AC XY: 1 AN XY: 132508

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: 15 AN: 1458476 Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5 AN XY: 725054

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.: 33

Alfa AF: 0.0000239 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

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

Aug 28, 2023

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

Invitae

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	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
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	D
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

Other links and lift over

dbSNP: rs369687307; hg19: chr7-151483556;