ENST00000418337.6:c.-21C>T

Variant names:

• chr7-151632120-G-A
• rs1476121151
• ENST00000418337.6:c.-21C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000418337.6(PRKAG2):​c.-21C>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 0.00000476 in 1,259,998 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRKAG2 ENST00000418337.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.76
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-151632120-G-A is Benign according to our data. Variant chr7-151632120-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533887.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.703C>T	p.Leu235Leu	synonymous	Exon 5 of 16	NP_057287.2
	PRKAG2	NM_001407034.1		c.-21C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001393963.1
	PRKAG2	NM_001407035.1		c.-21C>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.-21C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000387386.2	Q9UGJ0-2
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.703C>T	p.Leu235Leu	synonymous	Exon 5 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.571C>T	p.Leu191Leu	synonymous	Exon 5 of 16	ENSP00000376549.2	Q9UGJ0-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000610 AC: 1 AN: 163830 AF XY: 0.0000106

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000476 AC: 6 AN: 1259998 Hom.: 0 Cov.: 30 AF XY: 0.00000479 AC XY: 3 AN XY: 626076

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

American (AMR) AF: 0.00 AC: 0 AN: 32008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19948

East Asian (EAS) AF: 0.00 AC: 0 AN: 26704

South Asian (SAS) AF: 0.00 AC: 0 AN: 67242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4572

European-Non Finnish (NFE) AF: 0.00000599 AC: 6 AN: 1001200

Other (OTH) AF: 0.00 AC: 0 AN: 48632

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lethal congenital glycogen storage disease of heart (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		1.8
PromoterAI		0.15	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: rs1476121151;

hg19: chr7-151329206;