rs17313469

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000292.3(PHKA2):c.112G>C(p.Glu38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,210,349 control chromosomes in the GnomAD database, including 337 homozygotes. There are 10,659 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 24 hom., 656 hem., cov: 23)

Exomes 𝑓: 0.028 ( 313 hom. 10003 hem. )

Consequence

PHKA2
NM_000292.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.40

Publications

9 publications found

Variant links:

Genes affected

PHKA2 (HGNC:8926): (phosphorylase kinase regulatory subunit alpha 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, and the hepatic isoform is encoded by this gene. 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, which are encoded by two different genes. 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 9A, also known as X-linked liver glycogenosis. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined.[provided by RefSeq, Feb 2010]

PHKA2 Gene-Disease associations (from GenCC):

glycogen storage disease IXa1
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
glycogen storage disease due to liver phosphorylase kinase deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PHKA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008445859).

BP6

Variant X-18954379-C-G is Benign according to our data. Variant chrX-18954379-C-G is described in ClinVar as Benign. ClinVar VariationId is 255768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0203 (2291/112838) while in subpopulation NFE AF = 0.0293 (1565/53328). AF 95% confidence interval is 0.0281. There are 24 homozygotes in GnomAd4. There are 656 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3 link	c.112G>C	p.Glu38Gln	missense_variant	Exon 2 of 33	ENST00000379942.5	NP_000283.1	P46019

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5 link	c.112G>C	p.Glu38Gln	missense_variant	Exon 2 of 33	1	NM_000292.3	ENSP00000369274.4		P46019

Frequencies

GnomAD3 genomes

AF:

0.0203

AC:

2294

AN:

112782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00389

Gnomad AMI

AF:

0.0948

Gnomad AMR

AF:

0.0257

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.000561

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0553

Gnomad NFE

AF:

0.0293

Gnomad OTH

AF:

0.0304

GnomAD2 exomes

AF:

0.0198

AC:

3617

AN:

182784

AF XY:

0.0209

show subpopulations

Gnomad AFR exome

AF:

0.00403

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0326

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.0303

Gnomad OTH exome

AF:

0.0261

GnomAD4 exome

AF:

0.0283

AC:

31076

AN:

1097511

Hom.:

313

Cov.:

AF XY:

0.0276

AC XY:

10003

AN XY:

362935

show subpopulations

African (AFR)

AF:

0.00405

AC:

107

AN:

26390

American (AMR)

AF:

0.0152

AC:

536

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.0329

AC:

638

AN:

19383

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30205

South Asian (SAS)

AF:

0.00460

AC:

249

AN:

54131

European-Finnish (FIN)

AF:

0.0190

AC:

764

AN:

40237

Middle Eastern (MID)

AF:

0.0220

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0326

AC:

27437

AN:

841749

Other (OTH)

AF:

0.0272

AC:

1252

AN:

46078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1112

2225

3337

4450

5562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1052

2104

3156

4208

5260

<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:

0.0203

AC:

2291

AN:

112838

Hom.:

Cov.:

AF XY:

0.0187

AC XY:

656

AN XY:

34994

show subpopulations

African (AFR)

AF:

0.00388

AC:

121

AN:

31157

American (AMR)

AF:

0.0256

AC:

275

AN:

10731

Ashkenazi Jewish (ASJ)

AF:

0.0332

AC:

AN:

2651

East Asian (EAS)

AF:

0.000563

AC:

AN:

3554

South Asian (SAS)

AF:

0.00582

AC:

AN:

2751

European-Finnish (FIN)

AF:

0.0165

AC:

103

AN:

6230

Middle Eastern (MID)

AF:

0.0463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0293

AC:

1565

AN:

53328

Other (OTH)

AF:

0.0300

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

171

257

342

428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0283

Hom.:

609

Bravo

AF:

0.0218

TwinsUK

AF:

0.0324

AC:

120

ALSPAC

AF:

0.0312

AC:

ESP6500AA

AF:

0.00391

AC:

ESP6500EA

AF:

0.0360

AC:

242

ExAC

AF:

0.0202

AC:

2446

EpiCase

AF:

0.0346

EpiControl

AF:

0.0366

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 03, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Glycogen storage disease IXa1

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0084

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.90

PhyloP100

3.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.32

Sift

Benign

0.17

Sift4G

Benign

0.32

Polyphen

0.0030

Vest4

0.030

MPC

0.93

ClinPred

0.0084

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.60

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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