Genetic Variant PRKAG2:c.-46C>A (chr7-151632145-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016203.4(PRKAG2):c.685-7C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 1,391,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

PRKAG2
NM_016203.4 splice_region, intron

Scores

Splicing: ADA: 0.001312

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.170

Publications

1 publications found

Variant links:

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)

PRKAG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 7-151632145-G-T is Benign according to our data. Variant chr7-151632145-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45731.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000411 (51/1242180) while in subpopulation NFE AF = 0.0000514 (51/992360). AF 95% confidence interval is 0.0000397. There are 0 homozygotes in GnomAdExome4. There are 29 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 51 AD gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PRKAG2	NM_016203.4	MANE Select	c.685-7C>A	splice_region intron	N/A	NP_057287.2
PRKAG2	NM_001407035.1		c.-46C>A	5_prime_UTR	Exon 1 of 11	NP_001393964.1
PRKAG2	NM_001407036.1		c.-46C>A	5_prime_UTR	Exon 1 of 11	NP_001393965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PRKAG2	ENST00000418337.6	TSL:1	c.-46C>A	5_prime_UTR	Exon 1 of 12	ENSP00000387386.2	Q9UGJ0-2
PRKAG2	ENST00000287878.9	TSL:1 MANE Select	c.685-7C>A	splice_region intron	N/A	ENSP00000287878.3	Q9UGJ0-1
PRKAG2	ENST00000392801.6	TSL:1	c.553-7C>A	splice_region intron	N/A	ENSP00000376549.2	Q9UGJ0-3

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1242180

Hom.:

Cov.:

AF XY:

0.0000471

AC XY:

AN XY:

616254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25796

American (AMR)

AF:

0.00

AC:

AN:

30754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19474

East Asian (EAS)

AF:

0.00

AC:

AN:

26178

South Asian (SAS)

AF:

0.00

AC:

AN:

63592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4426

European-Non Finnish (NFE)

AF:

0.0000514

AC:

AN:

992360

Other (OTH)

AF:

0.00

AC:

AN:

47922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149756

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73030

show subpopulations

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

African (AFR)

AF:

0.0000243

AC:

AN:

41186

American (AMR)

AF:

0.00

AC:

AN:

15084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67074

Other (OTH)

AF:

0.00

AC:

AN:

2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Cardiomyopathy (1)

Lethal congenital glycogen storage disease of heart (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.17

PromoterAI

-0.087

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0013

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over