7-151557089-T-C

Variant names:

• chr7-151557089-T-C
• rs8961
• NM_016203.4:c.*112A>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.*112A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,515,240 control chromosomes in the GnomAD database, including 309,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24713 hom., cov: 32)
  • Exomes 𝑓: 0.64 (285247 hom.)
• Consequence: PRKAG2 NM_016203.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.139
• Publications: 21 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=-0.68).
• BP6: Variant 7-151557089-T-C is Benign according to our data. Variant chr7-151557089-T-C is described in ClinVar as Benign. ClinVar VariationId is 359342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.*112A>G		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.*112A>G		3_prime_UTR_variant	Exon 16 of 16	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83568 AN: 151966 Hom.: 24700 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.634

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.570

GnomAD4 exome AF: 0.643 AC: 876654 AN: 1363156 Hom.: 285247 Cov.: 20 AF XY: 0.644 AC XY: 439169 AN XY: 682248

African (AFR) AF: 0.295 AC: 9166 AN: 31112

American (AMR) AF: 0.520 AC: 22576 AN: 43454

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 16694 AN: 25306

East Asian (EAS) AF: 0.717 AC: 28005 AN: 39032

South Asian (SAS) AF: 0.638 AC: 53114 AN: 83230

European-Finnish (FIN) AF: 0.699 AC: 37046 AN: 52968

Middle Eastern (MID) AF: 0.612 AC: 3397 AN: 5554

European-Non Finnish (NFE) AF: 0.654 AC: 670419 AN: 1025466

Other (OTH) AF: 0.635 AC: 36237 AN: 57034

GnomAD4 genome AF: 0.550 AC: 83603 AN: 152084 Hom.: 24713 Cov.: 32 AF XY: 0.556 AC XY: 41358 AN XY: 74348

African (AFR) AF: 0.312 AC: 12958 AN: 41476

American (AMR) AF: 0.556 AC: 8500 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2311 AN: 3472

East Asian (EAS) AF: 0.714 AC: 3699 AN: 5182

South Asian (SAS) AF: 0.635 AC: 3053 AN: 4810

European-Finnish (FIN) AF: 0.692 AC: 7318 AN: 10572

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43994 AN: 67978

Other (OTH) AF: 0.575 AC: 1213 AN: 2110

Alfa AF: 0.607 Hom.: 37946

Bravo AF: 0.529

Asia WGS AF: 0.633 AC: 2203 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Hypertrophic cardiomyopathy 6 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.9
DANN	Benign	0.79
PhyloP100		0.14
Mutation Taster		=99/1	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: rs8961; hg19: chr7-151254175;