ENST00000418337.6:c.-4C>T

Variant names:

• chr7-151632103-G-A
• rs752351250
• ENST00000418337.6:c.-4C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000418337.6(PRKAG2):​c.-4C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000667 in 149,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRKAG2 ENST00000418337.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• Publications: 0 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 6

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

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

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000418337.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.720C>T	p.Ala240Ala	synonymous	Exon 5 of 16	NP_057287.2
	PRKAG2	NM_001407034.1		c.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001393963.1
	PRKAG2	NM_001407035.1		c.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001393964.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000418337.6	TSL:1	c.-4C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000387386.2	Q9UGJ0-2
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.720C>T	p.Ala240Ala	synonymous	Exon 5 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.588C>T	p.Ala196Ala	synonymous	Exon 5 of 16	ENSP00000376549.2	Q9UGJ0-3

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1265696 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 629168

African (AFR) AF: 0.00 AC: 0 AN: 26184

American (AMR) AF: 0.00 AC: 0 AN: 32174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20052

East Asian (EAS) AF: 0.00 AC: 0 AN: 26668

South Asian (SAS) AF: 0.00 AC: 0 AN: 68662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1003946

Other (OTH) AF: 0.00 AC: 0 AN: 48906

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149882 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73086

African (AFR) AF: 0.0000243 AC: 1 AN: 41210

American (AMR) AF: 0.00 AC: 0 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67066

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.87
PhyloP100		1.8
PromoterAI		-0.060	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs752351250;

hg19: chr7-151329189;