rs66628686

Variant names:

• chr7-151876646-G-A
• rs66628686
• NM_016203.4:c.-26C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016203.4(PRKAG2):​c.-26C>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 0.144 in 1,598,058 control chromosomes in the GnomAD database, including 18,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1807 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16659 hom.)
• Consequence: PRKAG2 NM_016203.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.52
• 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-AS1 (HGNC:40468): (PRKAG2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-151876646-G-A is Benign according to our data. Variant chr7-151876646-G-A is described in ClinVar as Benign. ClinVar VariationId is 260692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016203.4. 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.-26C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_057287.2
	PRKAG2	NM_016203.4	MANE Select	c.-26C>T		5_prime_UTR	Exon 1 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.-26C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001393950.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.-26C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.-26C>T		5_prime_UTR	Exon 1 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000488258.5	TSL:1	n.-26C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000420783.1	F8WDA1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22415 AN: 152038 Hom.: 1810 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.176 AC: 42586 AN: 242650 AF XY: 0.171

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.144 AC: 207749 AN: 1445902 Hom.: 16659 Cov.: 29 AF XY: 0.144 AC XY: 104027 AN XY: 720176

African (AFR) AF: 0.142 AC: 4718 AN: 33324

American (AMR) AF: 0.298 AC: 13313 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3482 AN: 26100

East Asian (EAS) AF: 0.247 AC: 9805 AN: 39636

South Asian (SAS) AF: 0.212 AC: 18275 AN: 86148

European-Finnish (FIN) AF: 0.165 AC: 7363 AN: 44596

Middle Eastern (MID) AF: 0.0479 AC: 276 AN: 5756

European-Non Finnish (NFE) AF: 0.128 AC: 141763 AN: 1105606

Other (OTH) AF: 0.146 AC: 8754 AN: 60098

GnomAD4 genome AF: 0.147 AC: 22415 AN: 152156 Hom.: 1807 Cov.: 32 AF XY: 0.150 AC XY: 11164 AN XY: 74400

African (AFR) AF: 0.136 AC: 5648 AN: 41508

American (AMR) AF: 0.217 AC: 3321 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 449 AN: 3470

East Asian (EAS) AF: 0.240 AC: 1241 AN: 5170

South Asian (SAS) AF: 0.224 AC: 1080 AN: 4818

European-Finnish (FIN) AF: 0.161 AC: 1704 AN: 10596

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8521 AN: 67992

Other (OTH) AF: 0.137 AC: 289 AN: 2116

Alfa AF: 0.143 Hom.: 986

Bravo AF: 0.153

Asia WGS AF: 0.247 AC: 857 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hypertrophic cardiomyopathy 6 (1)
-	-	1	Lethal congenital glycogen storage disease of heart (1)
-	-	1	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		1.5
PromoterAI		-0.061	Neutral
Mutation Taster		=300/0	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: rs66628686; hg19: chr7-151573731; COSMIC: COSV55222433; COSMIC: COSV55222433;