7-151557207-C-T

Variant names:

• chr7-151557207-C-T
• rs138167675
• NM_016203.4:c.1704G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016203.4(PRKAG2):​c.1704G>A​(p.Thr568Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T568T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -3.02
• Publications: 1 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 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, 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: Genomics England PanelApp
• Wolff-Parkinson-White syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-151557207-C-T is Benign according to our data. Variant chr7-151557207-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00139 (212/152274) while in subpopulation AFR AF = 0.00501 (208/41550). AF 95% confidence interval is 0.00445. There are 0 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 212 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016203.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.1704G>A	p.Thr568Thr	synonymous	Exon 16 of 16	NP_057287.2
	PRKAG2	NM_001407023.1		c.1701G>A	p.Thr567Thr	synonymous	Exon 16 of 16	NP_001393952.1	A0A494C155
	PRKAG2	NM_001040633.2		c.1572G>A	p.Thr524Thr	synonymous	Exon 16 of 16	NP_001035723.1	Q9UGJ0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.1704G>A	p.Thr568Thr	synonymous	Exon 16 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.1572G>A	p.Thr524Thr	synonymous	Exon 16 of 16	ENSP00000376549.2	Q9UGJ0-3
	PRKAG2	ENST00000418337.6	TSL:1	c.981G>A	p.Thr327Thr	synonymous	Exon 12 of 12	ENSP00000387386.2	Q9UGJ0-2

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000348 AC: 87 AN: 249704 AF XY: 0.000215

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461874 Hom.: 0 Cov.: 30 AF XY: 0.000146 AC XY: 106 AN XY: 727242

African (AFR) AF: 0.00535 AC: 179 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112000

Other (OTH) AF: 0.000447 AC: 27 AN: 60396

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74450

African (AFR) AF: 0.00501 AC: 208 AN: 41550

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 6 (1)
-	-	1	Lethal congenital glycogen storage disease of heart (1)
-	-	1	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.024
DANN	Benign	0.67
PhyloP100		-3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs138167675; hg19: chr7-151254293;