NM_016203.4:c.1199C>G

Variant names:

• chr7-151568750-G-C
• rs28938173
• NM_016203.4:c.1199C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_016203.4(PRKAG2):​c.1199C>G​(p.Thr400Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T400A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.74
• 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 6

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-151568750-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

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.1199C>G	p.Thr400Ser	missense	Exon 11 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.1199C>G	p.Thr400Ser	missense	Exon 11 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.1196C>G	p.Thr399Ser	missense	Exon 11 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.1199C>G	p.Thr400Ser	missense	Exon 11 of 16	ENSP00000287878.3	Q9UGJ0-1
	PRKAG2	ENST00000392801.6	TSL:1	c.1067C>G	p.Thr356Ser	missense	Exon 11 of 16	ENSP00000376549.2	Q9UGJ0-3
	PRKAG2	ENST00000418337.6	TSL:1	c.476C>G	p.Thr159Ser	missense	Exon 7 of 12	ENSP00000387386.2	Q9UGJ0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Uncertain	0.59
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.94	P
Vest4		0.88
MutPred		0.83		Gain of sheet (P = 0.1451)
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.58
gMVP		0.87
Mutation Taster		=54/46	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: rs28938173; hg19: chr7-151265836; COSMIC: COSV99836458; COSMIC: COSV99836458;