NM_016203.4:c.698C>T

Variant names:

• chr7-151632125-G-A
• rs201240745
• NM_016203.4:c.698C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016203.4(PRKAG2):​c.698C>T​(p.Ala233Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,252,222 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/23 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. A233G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2637236).

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.698C>T	p.Ala233Val	missense	Exon 5 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.698C>T	p.Ala233Val	missense	Exon 5 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.698C>T	p.Ala233Val	missense	Exon 5 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.698C>T	p.Ala233Val	missense	Exon 5 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.566C>T	p.Ala189Val	missense	Exon 5 of 16	ENSP00000376549.2
	PRKAG2	ENST00000418337.6	TSL:1	c.-26C>T		5_prime_UTR	Exon 1 of 12	ENSP00000387386.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000559 AC: 7 AN: 1252222 Hom.: 0 Cov.: 30 AF XY: 0.00000322 AC XY: 2 AN XY: 621718

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26060

American (AMR) AF: 0.00 AC: 0 AN: 31632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19742

East Asian (EAS) AF: 0.00 AC: 0 AN: 26508

South Asian (SAS) AF: 0.0000305 AC: 2 AN: 65680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4484

European-Non Finnish (NFE) AF: 0.00000501 AC: 5 AN: 997294

Other (OTH) AF: 0.00 AC: 0 AN: 48252

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000244801), which strongly suggests a high chance of mosaicism in these individuals.

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	0.10
CardioboostCm	Benign	0.010
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.28
Sift	Benign	0.33	T
Sift4G	Benign	0.33	T
Polyphen		0.012	B
Vest4		0.34
MutPred		0.40		Gain of catalytic residue at A233 (P = 0.087)
MVP		0.83
MPC		0.64
ClinPred		0.12	T
GERP RS		2.5
PromoterAI		-0.069	Neutral
Varity_R		0.072
gMVP		0.54
Mutation Taster		=87/13	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: rs201240745; hg19: chr7-151329211;