ENST00000418337.6:c.-46C>T

Variant names:

• chr7-151632145-G-A
• rs397517278
• ENST00000418337.6:c.-46C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000418337.6(PRKAG2):​c.-46C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,242,180 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: PRKAG2 ENST00000418337.6 5_prime_UTR
• Scores: Splicing: ADA: 0.00006706
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.170
• 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: G2P, 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: Genomics England PanelApp
• Wolff-Parkinson-White syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 7-151632145-G-A is Benign according to our data. Variant chr7-151632145-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 922288.Status of the report is criteria_provided_single_submitter, 1 stars.

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.685-7C>T		splice_region intron	N/A	NP_057287.2
	PRKAG2	NM_001407035.1		c.-46C>T		5_prime_UTR	Exon 1 of 11	NP_001393964.1
	PRKAG2	NM_001407036.1		c.-46C>T		5_prime_UTR	Exon 1 of 11	NP_001393965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000418337.6	TSL:1	c.-46C>T		5_prime_UTR	Exon 1 of 12	ENSP00000387386.2	Q9UGJ0-2
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.685-7C>T		splice_region intron	N/A	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.553-7C>T		splice_region intron	N/A	ENSP00000376549.2	Q9UGJ0-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000161 AC: 2 AN: 1242180 Hom.: 0 Cov.: 30 AF XY: 0.00000162 AC XY: 1 AN XY: 616254

African (AFR) AF: 0.00 AC: 0 AN: 25796

American (AMR) AF: 0.00 AC: 0 AN: 30754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19474

East Asian (EAS) AF: 0.00 AC: 0 AN: 26178

South Asian (SAS) AF: 0.0000157 AC: 1 AN: 63592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4426

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 992360

Other (OTH) AF: 0.00 AC: 0 AN: 47922

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		0.17
PromoterAI		-0.045	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.0040
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: rs397517278;

hg19: chr7-151329231;