rs2241053

Variant names:

• chr7-151568628-C-T
• rs2241053
• NM_016203.4:c.1233+88G>A

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.1233+88G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,423,952 control chromosomes in the GnomAD database, including 64,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10734 hom., cov: 32)
  • Exomes 𝑓: 0.28 (53609 hom.)
• Consequence: PRKAG2 NM_016203.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.712
• Publications: 7 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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, 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: PanelApp Australia, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-151568628-C-T is Benign according to our data. Variant chr7-151568628-C-T is described in ClinVar as Benign. ClinVar VariationId is 1244960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.1233+88G>A		intron_variant	Intron 11 of 15	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.1233+88G>A		intron_variant	Intron 11 of 15	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54057 AN: 151946 Hom.: 10698 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.281 AC: 357124 AN: 1271888 Hom.: 53609 AF XY: 0.280 AC XY: 178680 AN XY: 638608

African (AFR) AF: 0.539 AC: 15643 AN: 29000

American (AMR) AF: 0.422 AC: 17072 AN: 40502

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 10330 AN: 24228

East Asian (EAS) AF: 0.506 AC: 18546 AN: 36676

South Asian (SAS) AF: 0.274 AC: 21824 AN: 79658

European-Finnish (FIN) AF: 0.230 AC: 11352 AN: 49384

Middle Eastern (MID) AF: 0.325 AC: 1424 AN: 4380

European-Non Finnish (NFE) AF: 0.256 AC: 244728 AN: 954918

Other (OTH) AF: 0.305 AC: 16205 AN: 53142

GnomAD4 genome AF: 0.356 AC: 54148 AN: 152064 Hom.: 10734 Cov.: 32 AF XY: 0.355 AC XY: 26370 AN XY: 74324

African (AFR) AF: 0.527 AC: 21868 AN: 41506

American (AMR) AF: 0.382 AC: 5834 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1444 AN: 3468

East Asian (EAS) AF: 0.443 AC: 2291 AN: 5170

South Asian (SAS) AF: 0.287 AC: 1381 AN: 4816

European-Finnish (FIN) AF: 0.227 AC: 2393 AN: 10564

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17967 AN: 67964

Other (OTH) AF: 0.361 AC: 762 AN: 2112

Alfa AF: 0.307 Hom.: 9726

Bravo AF: 0.377

Asia WGS AF: 0.413 AC: 1437 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.074
DANN	Benign	0.59
PhyloP100		-0.71
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: rs2241053; hg19: chr7-151265714; COSMIC: COSV55225467; COSMIC: COSV55225467;