rs144857453

Variant names:

• chr7-151786526-C-A
• rs144857453
• NM_016203.4:c.130G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-151786526-C-A
• chr7-151786526-C-T

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.130G>T​(p.Ala44Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A44T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 11 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=0.2553565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAG2	NM_016203.4	c.130G>T	p.Ala44Ser	missense_variant	Exon 2 of 16	ENST00000287878.9	NP_057287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAG2	ENST00000287878.9	c.130G>T	p.Ala44Ser	missense_variant	Exon 2 of 16	1	NM_016203.4	ENSP00000287878.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247668 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460388 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726252

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111502

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.00061
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.18	N
REVEL	Uncertain	0.30
Sift	Benign	0.079	T
Sift4G	Benign	0.66	T
Polyphen		0.85	P
Vest4		0.42
MutPred		0.24		Gain of phosphorylation at A44 (P = 0.03);
MVP		0.64
MPC		0.19
ClinPred		0.65	D
GERP RS		5.3
Varity_R		0.10
gMVP		0.15
Mutation Taster		=85/15	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: rs144857453; hg19: chr7-151483612;