rs17714947

Variant names:

• chr7-151556749-G-A
• rs17714947
• NM_016203.4:c.*452C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016203.4(PRKAG2):​c.*452C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.037 in 161,174 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (158 hom., cov: 33)
  • Exomes 𝑓: 0.039 (14 hom.)
• Consequence: PRKAG2 NM_016203.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.46
• Publications: 4 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 7-151556749-G-A is Benign according to our data. Variant chr7-151556749-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 359336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.*452C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.*452C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5610 AN: 152158 Hom.: 158 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0395

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0588

GnomAD4 exome AF: 0.0390 AC: 347 AN: 8898 Hom.: 14 Cov.: 0 AF XY: 0.0386 AC XY: 184 AN XY: 4766

African (AFR) AF: 0.0172 AC: 2 AN: 116

American (AMR) AF: 0.0294 AC: 51 AN: 1732

Ashkenazi Jewish (ASJ) AF: 0.00962 AC: 1 AN: 104

East Asian (EAS) AF: 0.00 AC: 0 AN: 430

South Asian (SAS) AF: 0.0173 AC: 22 AN: 1270

European-Finnish (FIN) AF: 0.0339 AC: 4 AN: 118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.0531 AC: 253 AN: 4762

Other (OTH) AF: 0.0393 AC: 14 AN: 356

GnomAD4 genome AF: 0.0369 AC: 5612 AN: 152276 Hom.: 158 Cov.: 33 AF XY: 0.0349 AC XY: 2598 AN XY: 74456

African (AFR) AF: 0.0110 AC: 458 AN: 41552

American (AMR) AF: 0.0420 AC: 642 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4820

European-Finnish (FIN) AF: 0.0395 AC: 419 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0561 AC: 3818 AN: 68016

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0495 Hom.: 441

Bravo AF: 0.0369

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wolff-Parkinson-White pattern Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypertrophic cardiomyopathy 6 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.93
PhyloP100		4.5
Mutation Taster		=100/0	polymorphism

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: rs17714947; hg19: chr7-151253835;