rs148056866

chr7-151675583-G-Achr7-151675583-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_016203.4(PRKAG2):c.521C>T(p.Thr174Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T174A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 5.49

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0891341).
• BP6: Variant 7-151675583-G-A is Benign according to our data. Variant chr7-151675583-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164991.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000184 (28/152328) while in subpopulation AFR AF= 0.000649 (27/41588). AF 95% confidence interval is 0.000458. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.521C>T	p.Thr174Met	missense_variant	4/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.521C>T	p.Thr174Met	missense_variant	4/16	1	NM_016203.4	P3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251482 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135918

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727216

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74484

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000729 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 164991; Landrum et al., 2016) -

Cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 24, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 31, 2013

Variant classified as Uncertain Significance - Favor Benign. The Thr174Met varia nt in PRKAG2 has not been reported in individuals with cardiomyopathy, but has b een identified in 0.5% (1/192) of Kenyan chromosomes by the 1000 Genomes Project and in 3/4406 African American chromosomes by the NHLBI Exome Sequencing Projec t (http://evs.gs.washington.edu/EVS/; dbSNP rs148056866). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIF T) suggest that the Thr174Met variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. Although this data supports that the Thr174Met variant may be benign, additional studies are neede d to fully assess its clinical significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The p.T174M variant (also known as c.521C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 521. The threonine at codon 174 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in cardiac genetic testing cohorts; however, clinical details were limited and additional cardiac variants were detected in some cases (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:[ePub ahead of print]; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lethal congenital glycogen storage disease of heart Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
CardioboostCm	Benign	0.00088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.062	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.55	D;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.23	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.070	T;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.83	P;.;.
Vest4		0.30
MVP		0.67
MPC		0.14
ClinPred		0.052	T
GERP RS		5.4
Varity_R		0.052
gMVP		0.29

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: rs148056866; hg19: chr7-151372669;