chr7-151876533-T-G

Variant names:

• chr7-151876533-T-G
• rs756923555
• NM_016203.4:c.88A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The ENST00000287878.9(PRKAG2):​c.88A>C​(p.Arg30Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,608,230 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: PRKAG2 ENST00000287878.9 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.347
• 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-AS1 (HGNC:40468): (PRKAG2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 7-151876533-T-G is Benign according to our data. Variant chr7-151876533-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465343.
• BP7: Synonymous conserved (PhyloP=0.347 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000035 (51/1456296) while in subpopulation NFE AF = 0.000045 (50/1111902). AF 95% confidence interval is 0.0000346. There are 0 homozygotes in GnomAdExome4. There are 23 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 51 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000287878.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.88A>C	p.Arg30Arg	synonymous	Exon 1 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.88A>C	p.Arg30Arg	synonymous	Exon 1 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.88A>C	p.Arg30Arg	synonymous	Exon 1 of 15	NP_001393951.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.88A>C	p.Arg30Arg	synonymous	Exon 1 of 16	ENSP00000287878.3
	PRKAG2	ENST00000488258.5	TSL:1	n.88A>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000420783.1
	PRKAG2	ENST00000652321.2		c.88A>C	p.Arg30Arg	synonymous	Exon 1 of 16	ENSP00000498886.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000810 AC: 2 AN: 246830 AF XY: 0.00000746

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000350 AC: 51 AN: 1456296 Hom.: 0 Cov.: 32 AF XY: 0.0000317 AC XY: 23 AN XY: 724788

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111902

Other (OTH) AF: 0.0000166 AC: 1 AN: 60348

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151934 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74190

African (AFR) AF: 0.00 AC: 0 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 6 (1)
-	-	1	Lethal congenital glycogen storage disease of heart (1)
-	-	1	PRKAG2-related disorder (1)
-	1	-	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		0.35

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: rs756923555; hg19: chr7-151573618;