7-151556679-C-A

Position:

• chr7-151556679-C-A

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.*522G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 155,478 control chromosomes in the GnomAD database, including 25,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (24409 hom., cov: 34)
  • Exomes 𝑓: 0.59 (597 hom.)
• Consequence: PRKAG2 NM_016203.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.573

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=-0.94).
• BP6: Variant 7-151556679-C-A is Benign according to our data. Variant chr7-151556679-C-A is described in ClinVar as [Benign]. Clinvar id is 359335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.*522G>T		3_prime_UTR_variant	16/16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.*522G>T		3_prime_UTR_variant	16/16	1	NM_016203.4	ENSP00000287878	P3

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82803 AN: 152028 Hom.: 24397 Cov.: 34

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.587 AC: 1955 AN: 3332 Hom.: 597 Cov.: 0 AF XY: 0.598 AC XY: 1040 AN XY: 1740

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.471

Gnomad4 ASJ exome AF: 0.800

Gnomad4 EAS exome AF: 0.721

Gnomad4 SAS exome AF: 0.590

Gnomad4 FIN exome AF: 0.688

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.625

GnomAD4 genome AF: 0.544 AC: 82837 AN: 152146 Hom.: 24409 Cov.: 34 AF XY: 0.551 AC XY: 40967 AN XY: 74378

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.553

Gnomad4 ASJ AF: 0.666

Gnomad4 EAS AF: 0.714

Gnomad4 SAS AF: 0.633

Gnomad4 FIN AF: 0.692

Gnomad4 NFE AF: 0.645

Gnomad4 OTH AF: 0.570

Alfa AF: 0.623 Hom.: 29026

Bravo AF: 0.522

Asia WGS AF: 0.631 AC: 2194 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.94
CADD	Benign	3.1
DANN	Benign	0.59

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: rs1051956; hg19: chr7-151253765;