NM_000293.3:c.2309A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000293.3(PHKB):c.2309A>G(p.Tyr770Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,611,382 control chromosomes in the GnomAD database, including 2,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.069 ( 610 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1580 hom. )

Consequence

PHKB
NM_000293.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.19

Publications

21 publications found

Variant links:

Genes affected

PHKB (HGNC:8927): (phosphorylase kinase regulatory subunit beta) 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, encoded by two different genes. The beta subunit is the same in both the muscle and hepatic isoforms, encoded by this gene, which is a member of the phosphorylase b kinase regulatory subunit family. The gamma subunit also includes the skeletal muscle and hepatic isoforms, 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 9B, also known as phosphorylase kinase deficiency of liver and muscle. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. Two pseudogenes have been found on chromosomes 14 and 20, respectively.[provided by RefSeq, Feb 2010]

PHKB Gene-Disease associations (from GenCC):

glycogen storage disease IXb
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

PHKB 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=0.0038224757).

BP6

Variant 16-47663707-A-G is Benign according to our data. Variant chr16-47663707-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKB	NM_000293.3 link	c.2309A>G	p.Tyr770Cys	missense_variant	Exon 24 of 31	ENST00000323584.10	NP_000284.1	Q93100-1
PHKB	NM_001363837.1 link	c.2309A>G	p.Tyr770Cys	missense_variant	Exon 24 of 31		NP_001350766.1
PHKB	NM_001031835.3 link	c.2288A>G	p.Tyr763Cys	missense_variant	Exon 25 of 32		NP_001027005.1	Q93100-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10 link	c.2309A>G	p.Tyr770Cys	missense_variant	Exon 24 of 31	1	NM_000293.3	ENSP00000313504.5		Q93100-1

Frequencies

GnomAD3 genomes

AF:

0.0695

AC:

10578

AN:

152174

Hom.:

611

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0440

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.0138

Gnomad SAS

AF:

0.0283

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.0654

GnomAD2 exomes

AF:

0.0404

AC:

10154

AN:

251204

AF XY:

0.0393

show subpopulations

Gnomad AFR exome

AF:

0.156

Gnomad AMR exome

AF:

0.0280

Gnomad ASJ exome

AF:

0.0287

Gnomad EAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.0163

Gnomad NFE exome

AF:

0.0412

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0411

AC:

60021

AN:

1459090

Hom.:

1580

Cov.:

AF XY:

0.0405

AC XY:

29427

AN XY:

726024

show subpopulations

African (AFR)

AF:

0.157

AC:

5227

AN:

33370

American (AMR)

AF:

0.0295

AC:

1321

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

775

AN:

26122

East Asian (EAS)

AF:

0.00807

AC:

320

AN:

39652

South Asian (SAS)

AF:

0.0262

AC:

2258

AN:

86204

European-Finnish (FIN)

AF:

0.0156

AC:

834

AN:

53394

Middle Eastern (MID)

AF:

0.0561

AC:

323

AN:

5756

European-Non Finnish (NFE)

AF:

0.0417

AC:

46224

AN:

1109606

Other (OTH)

AF:

0.0454

AC:

2739

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2546

5092

7639

10185

12731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1776

3552

5328

7104

8880

<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:

0.0695

AC:

10583

AN:

152292

Hom.:

610

Cov.:

AF XY:

0.0674

AC XY:

5019

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.155

AC:

6455

AN:

41548

American (AMR)

AF:

0.0439

AC:

671

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3472

East Asian (EAS)

AF:

0.0137

AC:

AN:

5190

South Asian (SAS)

AF:

0.0277

AC:

134

AN:

4830

European-Finnish (FIN)

AF:

0.0182

AC:

193

AN:

10628

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0411

AC:

2794

AN:

68020

Other (OTH)

AF:

0.0652

AC:

138

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

481

962

1443

1924

2405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0496

Hom.:

968

Bravo

AF:

0.0759

TwinsUK

AF:

0.0388

AC:

144

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.152

AC:

671

ESP6500EA

AF:

0.0436

AC:

375

ExAC

AF:

0.0423

AC:

5138

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

EpiCase

AF:

0.0479

EpiControl

AF:

0.0469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 08, 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

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycogen storage disease IXb

Benign:3

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 13, 2017

Mayo Clinic Laboratories, Mayo Clinic

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

0.15

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

.;.;D;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.5

.;M;M;.

PhyloP100

8.2

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.0

D;D;D;.

REVEL

Pathogenic

0.88

Sift

Benign

0.11

T;T;T;.

Sift4G

Benign

0.097

T;T;T;T

Polyphen

0.91

P;.;B;.

Vest4

0.81

MPC

0.56

ClinPred

0.043

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.81

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.030

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