7-151632119-A-T

Variant names:

• chr7-151632119-A-T
• rs751094298
• NM_016203.4:c.704T>A

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.704T>A​(p.Leu235Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000794 in 1,258,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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. L235R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• 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=0.17126453).

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.704T>A	p.Leu235Gln	missense	Exon 5 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.704T>A	p.Leu235Gln	missense	Exon 5 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.704T>A	p.Leu235Gln	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.704T>A	p.Leu235Gln	missense	Exon 5 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.572T>A	p.Leu191Gln	missense	Exon 5 of 16	ENSP00000376549.2
	PRKAG2	ENST00000418337.6	TSL:1	c.-20T>A		5_prime_UTR	Exon 1 of 12	ENSP00000387386.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.94e-7 AC: 1 AN: 1258914 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 625520

⚠️ 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: 26140

American (AMR) AF: 0.00 AC: 0 AN: 31958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19904

East Asian (EAS) AF: 0.00 AC: 0 AN: 26662

South Asian (SAS) AF: 0.00 AC: 0 AN: 67182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4528

European-Non Finnish (NFE) AF: 9.99e-7 AC: 1 AN: 1000576

Other (OTH) AF: 0.00 AC: 0 AN: 48572

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
CardioboostCm	Uncertain	0.16
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.57
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.18
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.010	B
Vest4		0.24
MutPred		0.42		Gain of loop (P = 0.0312)
MVP		0.45
MPC		0.67
ClinPred		0.061	T
GERP RS		2.5
PromoterAI		-0.050	Neutral
Varity_R		0.088
gMVP		0.49
Mutation Taster		=90/10	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: rs751094298; hg19: chr7-151329205;