rs2302532

Variant names:

• chr7-151565219-A-C
• rs2302532
• NM_016203.4:c.1437+127T>G

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.1437+127T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 785,102 control chromosomes in the GnomAD database, including 26,891 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5026 hom., cov: 32)
  • Exomes 𝑓: 0.26 (21865 hom.)
• Consequence: PRKAG2 NM_016203.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0200
• Publications: 5 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-151565219-A-C is Benign according to our data. Variant chr7-151565219-A-C is described in ClinVar as Benign. ClinVar VariationId is 1221851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.298 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.1437+127T>G		intron	N/A	NP_057287.2
	PRKAG2	NM_001407021.1		c.1437+127T>G		intron	N/A	NP_001393950.1
	PRKAG2	NM_001407022.1		c.1434+127T>G		intron	N/A	NP_001393951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.1437+127T>G		intron	N/A	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.1305+127T>G		intron	N/A	ENSP00000376549.2	Q9UGJ0-3
	PRKAG2	ENST00000418337.6	TSL:1	c.714+127T>G		intron	N/A	ENSP00000387386.2	Q9UGJ0-2

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38865 AN: 151992 Hom.: 5021 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.259 AC: 164111 AN: 632992 Hom.: 21865 AF XY: 0.260 AC XY: 82896 AN XY: 319420

African (AFR) AF: 0.234 AC: 3313 AN: 14180

American (AMR) AF: 0.321 AC: 3361 AN: 10456

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 5669 AN: 13478

East Asian (EAS) AF: 0.291 AC: 6784 AN: 23286

South Asian (SAS) AF: 0.265 AC: 11110 AN: 41968

European-Finnish (FIN) AF: 0.210 AC: 6503 AN: 30934

Middle Eastern (MID) AF: 0.268 AC: 972 AN: 3624

European-Non Finnish (NFE) AF: 0.254 AC: 118647 AN: 466306

Other (OTH) AF: 0.270 AC: 7752 AN: 28760

GnomAD4 genome AF: 0.256 AC: 38894 AN: 152110 Hom.: 5026 Cov.: 32 AF XY: 0.256 AC XY: 19019 AN XY: 74358

African (AFR) AF: 0.226 AC: 9387 AN: 41514

American (AMR) AF: 0.305 AC: 4666 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1427 AN: 3470

East Asian (EAS) AF: 0.280 AC: 1446 AN: 5172

South Asian (SAS) AF: 0.277 AC: 1335 AN: 4820

European-Finnish (FIN) AF: 0.206 AC: 2180 AN: 10568

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17667 AN: 67972

Other (OTH) AF: 0.279 AC: 588 AN: 2108

Alfa AF: 0.263 Hom.: 816

Bravo AF: 0.263

Asia WGS AF: 0.308 AC: 1070 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.77
PhyloP100		-0.020
Mutation Taster		=100/0	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: rs2302532; hg19: chr7-151262305; COSMIC: COSV55232372; COSMIC: COSV55232372;