7-151559046-C-T

Variant names:

• chr7-151559046-C-T
• rs4726050
• NM_016203.4:c.1678+1478G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016203.4(PRKAG2):​c.1678+1478G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 985,176 control chromosomes in the GnomAD database, including 199,910 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.53 (23720 hom., cov: 33)
  • Exomes 𝑓: 0.65 (176190 hom.)
• Consequence: PRKAG2 NM_016203.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• PRKAG2-related cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• lethal congenital glycogen storage disease of heart

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• Wolff-Parkinson-White syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.1678+1478G>A		intron_variant	Intron 15 of 15	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1678+1478G>A		intron_variant	Intron 15 of 15	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80296 AN: 151978 Hom.: 23709 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.647 AC: 539062 AN: 833080 Hom.: 176190 Cov.: 43 AF XY: 0.647 AC XY: 248820 AN XY: 384706

African (AFR) AF: 0.193 AC: 3053 AN: 15786

American (AMR) AF: 0.553 AC: 544 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 3381 AN: 5152

East Asian (EAS) AF: 0.715 AC: 2596 AN: 3630

South Asian (SAS) AF: 0.642 AC: 10558 AN: 16458

European-Finnish (FIN) AF: 0.699 AC: 193 AN: 276

Middle Eastern (MID) AF: 0.593 AC: 959 AN: 1618

European-Non Finnish (NFE) AF: 0.657 AC: 500455 AN: 761882

Other (OTH) AF: 0.635 AC: 17323 AN: 27294

GnomAD4 genome AF: 0.528 AC: 80324 AN: 152096 Hom.: 23720 Cov.: 33 AF XY: 0.535 AC XY: 39743 AN XY: 74346

African (AFR) AF: 0.240 AC: 9971 AN: 41472

American (AMR) AF: 0.548 AC: 8386 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2279 AN: 3470

East Asian (EAS) AF: 0.715 AC: 3681 AN: 5150

South Asian (SAS) AF: 0.632 AC: 3048 AN: 4824

European-Finnish (FIN) AF: 0.691 AC: 7312 AN: 10576

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43916 AN: 67996

Other (OTH) AF: 0.559 AC: 1182 AN: 2114

Alfa AF: 0.611 Hom.: 15564

Bravo AF: 0.504

Asia WGS AF: 0.626 AC: 2178 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.84
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4726050; hg19: chr7-151256132;