rs139803629

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002637.4(PHKA1):c.2462G>A(p.Arg821His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,203,695 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,647 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 0.0027 ( 2 hom., 70 hem., cov: 22)

Exomes 𝑓: 0.0046 ( 10 hom. 1577 hem. )

Consequence

PHKA1
NM_002637.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.96

Variant links:

Genes affected

PHKA1 (HGNC:8925): (phosphorylase kinase regulatory subunit alpha 1) 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 skeletal muscle 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 9D, also known as X-linked muscle glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. A pseudogene has been found on chromosome 1.[provided by RefSeq, Feb 2010]

PHKA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009200335).

BP6

Variant X-72611092-C-T is Benign according to our data. Variant chrX-72611092-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-72611092-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00274 (305/111410) while in subpopulation NFE AF= 0.00496 (263/53061). AF 95% confidence interval is 0.00446. There are 2 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4 link	c.2462G>A	p.Arg821His	missense_variant	Exon 22 of 32	ENST00000373542.9	NP_002628.2	P46020-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9 link	c.2462G>A	p.Arg821His	missense_variant	Exon 22 of 32	1	NM_002637.4	ENSP00000362643.4		P46020-1

Frequencies

GnomAD3 genomes

AF:

0.00274

AC:

305

AN:

111357

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

AN XY:

33537

show subpopulations

Gnomad AFR

AF:

0.000783

Gnomad AMI

AF:

0.00876

Gnomad AMR

AF:

0.000768

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00496

Gnomad OTH

AF:

0.00201

GnomAD3 exomes

AF:

0.00331

AC:

605

AN:

182660

Hom.:

AF XY:

0.00316

AC XY:

213

AN XY:

67366

show subpopulations

Gnomad AFR exome

AF:

0.000685

Gnomad AMR exome

AF:

0.00132

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000316

Gnomad FIN exome

AF:

0.000814

Gnomad NFE exome

AF:

0.00638

Gnomad OTH exome

AF:

0.00445

GnomAD4 exome

AF:

0.00462

AC:

5043

AN:

1092285

Hom.:

Cov.:

AF XY:

0.00440

AC XY:

1577

AN XY:

358009

show subpopulations

Gnomad4 AFR exome

AF:

0.000609

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000259

Gnomad4 FIN exome

AF:

0.00116

Gnomad4 NFE exome

AF:

0.00564

Gnomad4 OTH exome

AF:

0.00427

GnomAD4 genome

AF:

0.00274

AC:

305

AN:

111410

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

AN XY:

33600

show subpopulations

Gnomad4 AFR

AF:

0.000781

Gnomad4 AMR

AF:

0.000767

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000167

Gnomad4 NFE

AF:

0.00496

Gnomad4 OTH

AF:

0.00199

Alfa

AF:

0.00440

Hom.:

181

Bravo

AF:

0.00277

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00312

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00431

AC:

ExAC

AF:

0.00400

AC:

486

EpiCase

AF:

0.00458

EpiControl

AF:

0.00547

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 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 IXd

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

D;D;.;.;D

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

D;T;T;T;T

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.0092

T;T;T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

1.7

L;.;L;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.4

D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.10

T;D;T;D;T

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.034

B;.;B;.;.

Vest4

0.12

MVP

0.77

MPC

0.38

ClinPred

0.022

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over