7-151557089-T-C

Position:

• chr7-151557089-T-C

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 0.139

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 -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 id is 359342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-151557089-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
PRKAG2	NM_016203.4	c.*112A>G		3_prime_UTR_variant	16/16	ENST00000287878.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRKAG2	ENST00000287878.9	c.*112A>G		3_prime_UTR_variant	16/16	1	NM_016203.4	P3

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

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.520

Gnomad4 ASJ exome AF: 0.660

Gnomad4 EAS exome AF: 0.717

Gnomad4 SAS exome AF: 0.638

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.654

Gnomad4 OTH exome AF: 0.635

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

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.666

Gnomad4 EAS AF: 0.714

Gnomad4 SAS AF: 0.635

Gnomad4 FIN AF: 0.692

Gnomad4 NFE AF: 0.647

Gnomad4 OTH AF: 0.575

Alfa AF: 0.621 Hom.: 30404

Bravo AF: 0.529

Asia WGS AF: 0.633 AC: 2203 AN: 3478

ClinVar

Significance: 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hypertrophic cardiomyopathy 6 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.9
DANN	Benign	0.79

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: rs8961; hg19: chr7-151254175;