rs12918964

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000293.3(PHKB):c.3121C>T(p.Arg1041Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,518,908 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1041Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0074 ( 6 hom., cov: 32)

Exomes 𝑓: 0.011 ( 105 hom. )

Consequence

PHKB
NM_000293.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.718

Publications

12 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=0.0072407722).

BP6

Variant 16-47698565-C-T is Benign according to our data. Variant chr16-47698565-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 319360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00736 (1043/141740) while in subpopulation NFE AF = 0.0128 (846/65928). AF 95% confidence interval is 0.0121. There are 6 homozygotes in GnomAd4. There are 470 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKB	NM_000293.3 link	c.3121C>T	p.Arg1041Trp	missense_variant	Exon 30 of 31	ENST00000323584.10	NP_000284.1	Q93100-1
PHKB	NM_001363837.1 link	c.3121C>T	p.Arg1041Trp	missense_variant	Exon 30 of 31		NP_001350766.1
PHKB	NM_001031835.3 link	c.3100C>T	p.Arg1034Trp	missense_variant	Exon 31 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.3121C>T	p.Arg1041Trp	missense_variant	Exon 30 of 31	1	NM_000293.3	ENSP00000313504.5		Q93100-1

Frequencies

GnomAD3 genomes

AF:

0.00737

AC:

1044

AN:

141718

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.0179

Gnomad AMR

AF:

0.00319

Gnomad ASJ

AF:

0.000593

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000684

Gnomad FIN

AF:

0.00532

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.00509

GnomAD2 exomes

AF:

0.00590

AC:

1455

AN:

246562

AF XY:

0.00594

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.00293

Gnomad ASJ exome

AF:

0.000502

Gnomad EAS exome

AF:

0.0000548

Gnomad FIN exome

AF:

0.00451

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00483

GnomAD4 exome

AF:

0.0109

AC:

15071

AN:

1377168

Hom.:

105

Cov.:

AF XY:

0.0105

AC XY:

7206

AN XY:

687628

show subpopulations

African (AFR)

AF:

0.00186

AC:

AN:

31118

American (AMR)

AF:

0.00314

AC:

136

AN:

43290

Ashkenazi Jewish (ASJ)

AF:

0.000122

AC:

AN:

24512

East Asian (EAS)

AF:

0.0000823

AC:

AN:

36472

South Asian (SAS)

AF:

0.000499

AC:

AN:

84158

European-Finnish (FIN)

AF:

0.00458

AC:

227

AN:

49604

Middle Eastern (MID)

AF:

0.00136

AC:

AN:

5146

European-Non Finnish (NFE)

AF:

0.0133

AC:

13935

AN:

1046646

Other (OTH)

AF:

0.0117

AC:

660

AN:

56222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

605

1210

1814

2419

3024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00736

AC:

1043

AN:

141740

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

470

AN XY:

68314

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

38768

American (AMR)

AF:

0.00318

AC:

AN:

14130

Ashkenazi Jewish (ASJ)

AF:

0.000593

AC:

AN:

3370

East Asian (EAS)

AF:

0.00

AC:

AN:

4712

South Asian (SAS)

AF:

0.000687

AC:

AN:

4364

European-Finnish (FIN)

AF:

0.00532

AC:

AN:

7330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0128

AC:

846

AN:

65928

Other (OTH)

AF:

0.00505

AC:

AN:

1982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00970

Hom.:

Bravo

AF:

0.00674

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.00573

AC:

695

Asia WGS

AF:

0.00116

AC:

AN:

3474

EpiCase

AF:

0.0101

EpiControl

AF:

0.00946

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease IXb

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Dec 12, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PHKB: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 10, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 10, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;.;T

Eigen

Benign

0.0019

Eigen_PC

Benign

0.047

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.2

.;M;M

PhyloP100

0.72

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.041

D;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.99

D;.;P

Vest4

0.24

MVP

0.78

MPC

0.28

ClinPred

0.035

GERP RS

3.0

Varity_R

0.047

gMVP

0.37

Mutation Taster

=100/0

polymorphism

(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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rs12918964

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