rs116605521

Variant names:

• chr7-151876562-C-A
• rs116605521
• NM_016203.4:c.59G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-151876562-C-A
• chr7-151876562-C-T

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.59G>T​(p.Ser20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,610,382 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S20S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (90 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.63
• Publications: 6 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-AS1 (HGNC:40468): (PRKAG2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016042292).
• BP6: Variant 7-151876562-C-A is Benign according to our data. Variant chr7-151876562-C-A is described in ClinVar as Benign. ClinVar VariationId is 45727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

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.59G>T	p.Ser20Ile	missense	Exon 1 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.59G>T	p.Ser20Ile	missense	Exon 1 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.59G>T	p.Ser20Ile	missense	Exon 1 of 15	NP_001393951.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.59G>T	p.Ser20Ile	missense	Exon 1 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000488258.5	TSL:1	n.59G>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000420783.1	F8WDA1
	PRKAG2	ENST00000652321.2		c.59G>T	p.Ser20Ile	missense	Exon 1 of 16	ENSP00000498886.2	A0A494C155

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3070 AN: 152210 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0687

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00515 AC: 1281 AN: 248542 AF XY: 0.00401

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00202 AC: 2951 AN: 1458054 Hom.: 90 Cov.: 32 AF XY: 0.00174 AC XY: 1266 AN XY: 725600

African (AFR) AF: 0.0699 AC: 2339 AN: 33474

American (AMR) AF: 0.00496 AC: 222 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49686

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000908 AC: 101 AN: 1111948

Other (OTH) AF: 0.00447 AC: 270 AN: 60372

GnomAD4 genome AF: 0.0202 AC: 3077 AN: 152328 Hom.: 120 Cov.: 32 AF XY: 0.0199 AC XY: 1479 AN XY: 74484

African (AFR) AF: 0.0687 AC: 2858 AN: 41580

American (AMR) AF: 0.0115 AC: 176 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68026

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00731 Hom.: 59

Bravo AF: 0.0229

ESP6500AA AF: 0.0706 AC: 311

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00643 AC: 781

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.36	T
Polyphen		0.072	B
Vest4		0.23
MVP		0.55
MPC		1.4
ClinPred		0.073	T
GERP RS		3.2
Varity_R		0.17
gMVP		0.35
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: rs116605521; hg19: chr7-151573647;