NM_000292.3:c.3027+48C>A

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.3027+48C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 837,108 control chromosomes in the GnomAD database, including 3 homozygotes. There are 322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 26 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 3 hom. 296 hem. )

Consequence

PHKA2
NM_000292.3 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.95

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-18901437-G-T is Benign according to our data. Variant chrX-18901437-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 255776.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 = 0.00109 (121/111282) while in subpopulation AMR AF = 0.002 (21/10485). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 26 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3 link	c.3027+48C>A		intron_variant	Intron 27 of 32	ENST00000379942.5	NP_000283.1	P46019

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHKA2	ENST00000379942.5 link	c.3027+48C>A	intron_variant	Intron 27 of 32	1	NM_000292.3	ENSP00000369274.4	P46019
PHKA2	ENST00000469645.5 link	n.511+48C>A	intron_variant	Intron 5 of 6	5
PHKA2	ENST00000473739.5 link	n.119+48C>A	intron_variant	Intron 1 of 5	3
PHKA2	ENST00000486231.2 link	n.296+48C>A	intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

121

AN:

111230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00201

Gnomad ASJ

AF:

0.00227

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000385

Gnomad FIN

AF:

0.000334

Gnomad MID

AF:

0.00833

Gnomad NFE

AF:

0.00136

Gnomad OTH

AF:

0.00533

GnomAD2 exomes

AF:

0.00124

AC:

226

AN:

182535

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00307

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000391

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.00464

GnomAD4 exome

AF:

0.00119

AC:

864

AN:

725826

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

296

AN XY:

212428

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

19117

American (AMR)

AF:

0.00153

AC:

AN:

34676

Ashkenazi Jewish (ASJ)

AF:

0.00275

AC:

AN:

17081

East Asian (EAS)

AF:

0.00

AC:

AN:

28392

South Asian (SAS)

AF:

0.000576

AC:

AN:

46862

European-Finnish (FIN)

AF:

0.000578

AC:

AN:

39820

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

3455

European-Non Finnish (NFE)

AF:

0.00117

AC:

588

AN:

502659

Other (OTH)

AF:

0.00178

AC:

AN:

33764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00109

AC:

121

AN:

111282

Hom.:

Cov.:

AF XY:

0.000777

AC XY:

AN XY:

33466

show subpopulations

African (AFR)

AF:

0.000294

AC:

AN:

30660

American (AMR)

AF:

0.00200

AC:

AN:

10485

Ashkenazi Jewish (ASJ)

AF:

0.00227

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3516

South Asian (SAS)

AF:

0.000386

AC:

AN:

2589

European-Finnish (FIN)

AF:

0.000334

AC:

AN:

5995

Middle Eastern (MID)

AF:

0.00913

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00136

AC:

AN:

52973

Other (OTH)

AF:

0.00526

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00109

Hom.:

Bravo

AF:

0.00122

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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

-0.81

CADD

Benign

7.6

(source)

DANN

Benign

0.53

PhyloP100

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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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