rs149991825

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.1952C>A(p.Thr651Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,200,405 control chromosomes in the GnomAD database, including 22 homozygotes. There are 1,290 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 0 hom., 119 hem., cov: 23)

Exomes 𝑓: 0.0034 ( 22 hom. 1171 hem. )

Consequence

PHKA2
NM_000292.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.00300

Publications

1 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=0.00387156).

BP6

Variant X-18920043-G-T is Benign according to our data. Variant chrX-18920043-G-T is described in ClinVar as Benign. ClinVar VariationId is 255770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00346 (388/112099) while in subpopulation AMR AF = 0.0186 (196/10563). AF 95% confidence interval is 0.0164. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 119 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3 link	c.1952C>A	p.Thr651Asn	missense_variant	Exon 18 of 33	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5 link	c.1952C>A	p.Thr651Asn	missense_variant	Exon 18 of 33	1	NM_000292.3	ENSP00000369274.4

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

389

AN:

112049

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000876

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.00264

Gnomad EAS

AF:

0.00196

Gnomad SAS

AF:

0.000371

Gnomad FIN

AF:

0.00181

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00242

Gnomad OTH

AF:

0.00601

GnomAD2 exomes

AF:

0.00573

AC:

1043

AN:

182026

AF XY:

0.00478

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0259

Gnomad ASJ exome

AF:

0.000935

Gnomad EAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00244

Gnomad NFE exome

AF:

0.00279

Gnomad OTH exome

AF:

0.00487

GnomAD4 exome

AF:

0.00335

AC:

3649

AN:

1088306

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

1171

AN XY:

354456

show subpopulations

African (AFR)

AF:

0.000305

AC:

AN:

26252

American (AMR)

AF:

0.0270

AC:

950

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

19327

East Asian (EAS)

AF:

0.00292

AC:

AN:

30186

South Asian (SAS)

AF:

0.000779

AC:

AN:

53936

European-Finnish (FIN)

AF:

0.00242

AC:

AN:

39726

Middle Eastern (MID)

AF:

0.000972

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.00274

AC:

2287

AN:

833782

Other (OTH)

AF:

0.00336

AC:

154

AN:

45786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

131

262

392

523

654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00346

AC:

388

AN:

112099

Hom.:

Cov.:

AF XY:

0.00347

AC XY:

119

AN XY:

34275

show subpopulations

African (AFR)

AF:

0.000874

AC:

AN:

30905

American (AMR)

AF:

0.0186

AC:

196

AN:

10563

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

2651

East Asian (EAS)

AF:

0.00197

AC:

AN:

3557

South Asian (SAS)

AF:

0.000744

AC:

AN:

2689

European-Finnish (FIN)

AF:

0.00181

AC:

AN:

6082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00242

AC:

129

AN:

53237

Other (OTH)

AF:

0.00594

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00285

Hom.:

125

Bravo

AF:

0.00537

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00277

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.00471

AC:

572

EpiCase

AF:

0.00338

EpiControl

AF:

0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 11, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 05, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

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

- -

Glycogen storage disease IXa1

Benign:1

Jan 21, 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

0.067

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.52

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.31

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.0

PhyloP100

-0.0030

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.43

REVEL

Benign

0.14

Sift

Benign

0.42

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.031

MVP

0.25

MPC

0.25

ClinPred

0.0031

GERP RS

-1.3

Varity_R

0.072

gMVP

0.58

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over