rs1289045435

Variant names:

• chr7-151675439-T-A
• rs1289045435
• NM_016203.4:c.665A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-151675439-T-A
• chr7-151675439-T-C
• chr7-151675439-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016203.4(PRKAG2):​c.665A>T​(p.His222Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H222P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• Publications: 0 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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 6

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24447283).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.665A>T	p.His222Leu	missense	Exon 4 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.665A>T	p.His222Leu	missense	Exon 4 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.665A>T	p.His222Leu	missense	Exon 4 of 15	NP_001393951.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.665A>T	p.His222Leu	missense	Exon 4 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.533A>T	p.His178Leu	missense	Exon 4 of 16	ENSP00000376549.2
	PRKAG2	ENST00000488258.5	TSL:1	n.665A>T		non_coding_transcript_exon	Exon 4 of 10	ENSP00000420783.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lethal congenital glycogen storage disease of heart (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
CardioboostCm	Benign	0.0059
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.53
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.19
Sift	Benign	0.65	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.33		Loss of helix (P = 0.079)
MVP		0.76
MPC		0.78
ClinPred		0.041	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.27
Mutation Taster		=96/4	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: rs1289045435; hg19: chr7-151372525;