rs61746358

Variant names:

• chr7-151781368-G-A
• rs61746358
• NM_016203.4:c.250C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-151781368-G-A
• chr7-151781368-G-C
• chr7-151781368-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016203.4(PRKAG2):​c.250C>T​(p.Arg84Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,613,010 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 7.10
• Publications: 5 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• 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, PanelApp Australia
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034148216).
• BP6: Variant 7-151781368-G-A is Benign according to our data. Variant chr7-151781368-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178108.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000499 (76/152292) while in subpopulation AFR AF = 0.00173 (72/41558). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 76 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.250C>T	p.Arg84Trp	missense	Exon 3 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.250C>T	p.Arg84Trp	missense	Exon 3 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.250C>T	p.Arg84Trp	missense	Exon 3 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.250C>T	p.Arg84Trp	missense	Exon 3 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.118C>T	p.Arg40Trp	missense	Exon 3 of 16	ENSP00000376549.2	Q9UGJ0-3
	PRKAG2	ENST00000488258.5	TSL:1	n.250C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000420783.1	F8WDA1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00174

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000147 AC: 36 AN: 244326 AF XY: 0.000120

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000457

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1460718 Hom.: 0 Cov.: 33 AF XY: 0.0000399 AC XY: 29 AN XY: 726624

African (AFR) AF: 0.00125 AC: 42 AN: 33474

American (AMR) AF: 0.0000673 AC: 3 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52958

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111642

Other (OTH) AF: 0.0000497 AC: 3 AN: 60326

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74464

African (AFR) AF: 0.00173 AC: 72 AN: 41558

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000540

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Cardiomyopathy (2)
-	1	1	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Lethal congenital glycogen storage disease of heart (1)
-	-	1	PRKAG2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.0026
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.034	T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.036	D
Polyphen		0.98	D
Vest4		0.51
MVP		0.53
MPC		0.34
ClinPred		0.092	T
GERP RS		4.6
Varity_R		0.10
gMVP		0.26
Mutation Taster		=78/22	polymorphism

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: rs61746358; hg19: chr7-151478454;