chr16-30756714-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The NM_000294.3(PHKG2):c.926G>A(p.Arg309Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000867 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R309W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

PHKG2
NM_000294.3 missense, splice_region

Scores

Splicing: ADA: 0.9937

Clinical Significance

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

Conservation

PhyloP100: 5.31

Publications

8 publications found

Variant links:

Genes affected

PHKG2 (HGNC:8931): (phosphorylase kinase catalytic subunit gamma 2) Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, encoded by two different genes. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, and the hepatic isoform is encoded by this gene. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9C, also known as autosomal liver glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

PHKG2 Gene-Disease associations (from GenCC):

glycogen storage disease IXc
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
glycogen storage disease due to liver phosphorylase kinase deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PHKG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 chr16-30756713-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2445869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 16-30756714-G-A is Pathogenic according to our data. Variant chr16-30756714-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253061.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKG2	NM_000294.3 link	c.926G>A	p.Arg309Gln	missense_variant, splice_region_variant	Exon 9 of 10	ENST00000563588.6	NP_000285.1	P15735-1
PHKG2	NM_001172432.2 link	c.926G>A	p.Arg309Gln	missense_variant, splice_region_variant	Exon 9 of 11		NP_001165903.1	P15735-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKG2	ENST00000563588.6 link	c.926G>A	p.Arg309Gln	missense_variant, splice_region_variant	Exon 9 of 10	1	NM_000294.3	ENSP00000455607.1		P15735-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000797

AC:

AN:

251014

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000104

AC:

116

AN:

1112010

Other (OTH)

AF:

0.0000993

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.0000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.0000906

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mauriac syndrome

Pathogenic:1

Jan 19, 2016

Childrens Diabetes Center, University of Wisconsin-Madison

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1

Aug 07, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PHKG2 c.926G>A (p.Arg309Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-05 in 251014 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PHKG2 causing Glycogen Phosphorylase Kinase Deficiency (8e-05 vs 0.0011), allowing no conclusion about variant significance. c.926G>A has been reported in the literature in a heterozygous individual affected with Mauriac disease (e.g. MacDonald_2016). This report does not provide unequivocal conclusions about association of the variant with Glycogen Phosphorylase Kinase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced enzyme activity and partial inhibition of glycogen breakdown under low glucose conditions in vitro (e.g. MacDonald_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27207549). ClinVar contains an entry for this variant (Variation ID: 253061). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Oct 28, 2016

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Glycogen storage disease IXc

Uncertain:1

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 309 of the PHKG2 protein (p.Arg309Gln). This variant is present in population databases (rs572115942, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of glycogen storage disease (PMID: 27207549). ClinVar contains an entry for this variant (Variation ID: 253061). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PHKG2 function (PMID: 27207549). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.99

L;L;.

PhyloP100

5.3

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.58

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.26

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.99

D;D;.

Vest4

0.49

MVP

0.72

MPC

0.84

ClinPred

0.22

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.12

gMVP

0.59

Mutation Taster

=53/47

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.86

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over