NM_000292.3:c.2532G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000292.3(PHKA2):c.2532G>A(p.Leu844Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,182,524 control chromosomes in the GnomAD database, including 96 homozygotes. There are 5,145 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 7 hom., 270 hem., cov: 23)

Exomes 𝑓: 0.014 ( 89 hom. 4875 hem. )

Consequence

PHKA2
NM_000292.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.752

Publications

0 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant X-18907083-C-T is Benign according to our data. Variant chrX-18907083-C-T is described in ClinVar as Benign. ClinVar VariationId is 255774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.752 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00924 (1037/112242) while in subpopulation NFE AF = 0.0157 (836/53160). AF 95% confidence interval is 0.0148. There are 7 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3 link	c.2532G>A	p.Leu844Leu	synonymous_variant	Exon 23 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.2532G>A	p.Leu844Leu	synonymous_variant	Exon 23 of 33	1	NM_000292.3	ENSP00000369274.4		P46019

Frequencies

GnomAD3 genomes

AF:

0.00924

AC:

1037

AN:

112186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00204

Gnomad AMI

AF:

0.00586

Gnomad AMR

AF:

0.00508

Gnomad ASJ

AF:

0.00452

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00371

Gnomad FIN

AF:

0.00729

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.00797

GnomAD2 exomes

AF:

0.00939

AC:

1297

AN:

138133

AF XY:

0.00951

show subpopulations

Gnomad AFR exome

AF:

0.00201

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00452

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00972

Gnomad NFE exome

AF:

0.0163

Gnomad OTH exome

AF:

0.00978

GnomAD4 exome

AF:

0.0143

AC:

15344

AN:

1070282

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

4875

AN XY:

345606

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

25841

American (AMR)

AF:

0.00389

AC:

121

AN:

31093

Ashkenazi Jewish (ASJ)

AF:

0.00408

AC:

AN:

18874

East Asian (EAS)

AF:

0.00

AC:

AN:

28884

South Asian (SAS)

AF:

0.00455

AC:

232

AN:

50972

European-Finnish (FIN)

AF:

0.0117

AC:

457

AN:

38939

Middle Eastern (MID)

AF:

0.00797

AC:

AN:

3888

European-Non Finnish (NFE)

AF:

0.0168

AC:

13868

AN:

826747

Other (OTH)

AF:

0.0111

AC:

502

AN:

45044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

510

1019

1529

2038

2548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

532

1064

1596

2128

2660

<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:

0.00924

AC:

1037

AN:

112242

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

270

AN XY:

34398

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

30941

American (AMR)

AF:

0.00507

AC:

AN:

10642

Ashkenazi Jewish (ASJ)

AF:

0.00452

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00372

AC:

AN:

2687

European-Finnish (FIN)

AF:

0.00729

AC:

AN:

6176

Middle Eastern (MID)

AF:

0.00465

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0157

AC:

836

AN:

53160

Other (OTH)

AF:

0.00786

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0117

Hom.:

Bravo

AF:

0.00887

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 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 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.0

(source)

DANN

Benign

0.59

PhyloP100

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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