rs143732206

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.2077A>G(p.Ile693Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00973 in 1,208,559 control chromosomes in the GnomAD database, including 45 homozygotes. There are 3,989 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 1 hom., 200 hem., cov: 23)

Exomes 𝑓: 0.010 ( 44 hom. 3789 hem. )

Consequence

PHKA2
NM_000292.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.319

Publications

6 publications found

Variant links:

COSMIC-nc: COSV108223416

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=0.00425151).

BP6

Variant X-18918741-T-C is Benign according to our data. Variant chrX-18918741-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00676 (759/112314) while in subpopulation SAS AF = 0.016 (43/2691). AF 95% confidence interval is 0.0122. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 200 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3 link	c.2077A>G	p.Ile693Val	missense_variant	Exon 19 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.2077A>G	p.Ile693Val	missense_variant	Exon 19 of 33	1	NM_000292.3	ENSP00000369274.4		P46019

Frequencies

GnomAD3 genomes

AF:

0.00676

AC:

759

AN:

112260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.0161

Gnomad AMR

AF:

0.00274

Gnomad ASJ

AF:

0.00491

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00995

GnomAD2 exomes

AF:

0.00769

AC:

1411

AN:

183395

AF XY:

0.00911

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00574

Gnomad EAS exome

AF:

0.0000721

Gnomad FIN exome

AF:

0.00131

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00662

GnomAD4 exome

AF:

0.0100

AC:

10995

AN:

1096245

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

3789

AN XY:

361675

show subpopulations

African (AFR)

AF:

0.00163

AC:

AN:

26368

American (AMR)

AF:

0.00267

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00578

AC:

112

AN:

19377

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30198

South Asian (SAS)

AF:

0.0165

AC:

891

AN:

54105

European-Finnish (FIN)

AF:

0.00178

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.0271

AC:

112

AN:

4128

European-Non Finnish (NFE)

AF:

0.0110

AC:

9285

AN:

840289

Other (OTH)

AF:

0.00836

AC:

385

AN:

46042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

350

701

1051

1402

1752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.00676

AC:

759

AN:

112314

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

200

AN XY:

34480

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

30948

American (AMR)

AF:

0.00274

AC:

AN:

10597

Ashkenazi Jewish (ASJ)

AF:

0.00491

AC:

AN:

2647

East Asian (EAS)

AF:

0.000280

AC:

AN:

3575

South Asian (SAS)

AF:

0.0160

AC:

AN:

2691

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

6171

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0112

AC:

596

AN:

53257

Other (OTH)

AF:

0.00982

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

109

136

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:

0.0100

Hom.:

503

Bravo

AF:

0.00628

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.0111

AC:

ExAC

AF:

0.00874

AC:

1061

EpiCase

AF:

0.0107

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 05, 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

- -

Glycogen storage disease IXa1

Benign:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.0040

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.21

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-1.1

PhyloP100

0.32

PrimateAI

Benign

0.32

PROVEAN

Benign

0.010

REVEL

Benign

0.27

Sift

Benign

0.80

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.028

MVP

0.29

MPC

0.18

ClinPred

0.0015

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.26

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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