rs201735117

Variant names:

• chr7-151632073-G-A
• rs201735117
• NM_016203.4:c.750C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_016203.4(PRKAG2):​c.750C>T​(p.Asp250Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,403,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: PRKAG2 NM_016203.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.316
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 7-151632073-G-A is Benign according to our data. Variant chr7-151632073-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378428.
• BP7: Synonymous conserved (PhyloP=-0.316 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000999 (15/150174) while in subpopulation EAS AF = 0.00175 (9/5150). AF 95% confidence interval is 0.000911. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKAG2	NM_016203.4	MANE Select	c.750C>T	p.Asp250Asp	synonymous	Exon 5 of 16	NP_057287.2
	PRKAG2	NM_001407021.1		c.750C>T	p.Asp250Asp	synonymous	Exon 5 of 15	NP_001393950.1
	PRKAG2	NM_001407022.1		c.750C>T	p.Asp250Asp	synonymous	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.750C>T	p.Asp250Asp	synonymous	Exon 5 of 16	ENSP00000287878.3
	PRKAG2	ENST00000392801.6	TSL:1	c.618C>T	p.Asp206Asp	synonymous	Exon 5 of 16	ENSP00000376549.2
	PRKAG2	ENST00000418337.6	TSL:1	c.27C>T	p.Asp9Asp	synonymous	Exon 1 of 12	ENSP00000387386.2

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 16 AN: 150068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000102

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000596

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000123 AC: 20 AN: 162340 AF XY: 0.0000969

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000428

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000144 AC: 181 AN: 1253214 Hom.: 0 Cov.: 30 AF XY: 0.000151 AC XY: 94 AN XY: 622134

African (AFR) AF: 0.00 AC: 0 AN: 25990

American (AMR) AF: 0.0000318 AC: 1 AN: 31472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19722

East Asian (EAS) AF: 0.00510 AC: 134 AN: 26266

South Asian (SAS) AF: 0.000137 AC: 9 AN: 65768

European-Finnish (FIN) AF: 0.0000295 AC: 1 AN: 33842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4456

European-Non Finnish (NFE) AF: 0.0000301 AC: 30 AN: 997382

Other (OTH) AF: 0.000124 AC: 6 AN: 48316

GnomAD4 genome AF: 0.0000999 AC: 15 AN: 150174 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 8 AN XY: 73302

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000102 AC: 1 AN: 9844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000596 AC: 4 AN: 67156

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy 6 (1)
-	-	1	Lethal congenital glycogen storage disease of heart (1)
-	-	1	not specified (1)
-	-	1	PRKAG2-related disorder (1)
-	1	-	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.93
PhyloP100		-0.32
PromoterAI		-0.073	Neutral

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: rs201735117; hg19: chr7-151329159;