chr7-151556749-G-A

Position:

• chr7-151556749-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.*452C>T		3_prime_UTR_variant	16/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.*452C>T		3_prime_UTR_variant	16/16	1	NM_016203.4	P3

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

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.0294

Gnomad4 ASJ exome AF: 0.00962

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.0339

Gnomad4 NFE exome AF: 0.0531

Gnomad4 OTH exome AF: 0.0393

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

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0420

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0395

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0511 Hom.: 298

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hypertrophic cardiomyopathy 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs17714947; hg19: chr7-151253835;