dbSNP rs139738333: PHKB:p.Asn173Ser (chr16-47515525-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000293.3(PHKB):c.518A>G(p.Asn173Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,386,756 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 8 hom. )

Consequence

PHKB
NM_000293.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 7.73

Publications

6 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, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

PHKB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023494244).

BP6

Variant 16-47515525-A-G is Benign according to our data. Variant chr16-47515525-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198068.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00201 (306/152296) while in subpopulation NFE AF = 0.00326 (222/68022). AF 95% confidence interval is 0.00291. There are 1 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHKB	NM_000293.3	MANE Select	c.518A>G	p.Asn173Ser	missense	Exon 6 of 31	NP_000284.1	Q93100-1
PHKB	NM_001363837.1		c.518A>G	p.Asn173Ser	missense	Exon 6 of 31	NP_001350766.1	Q93100-3
PHKB	NM_001031835.3		c.497A>G	p.Asn166Ser	missense	Exon 7 of 32	NP_001027005.1	Q93100-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHKB	ENST00000323584.10	TSL:1 MANE Select	c.518A>G	p.Asn173Ser	missense	Exon 6 of 31	ENSP00000313504.5	Q93100-1
PHKB	ENST00000566044.5	TSL:1	c.497A>G	p.Asn166Ser	missense	Exon 7 of 32	ENSP00000456729.1	Q93100-4
PHKB	ENST00000567402.5	TSL:1	n.533A>G		non_coding_transcript_exon	Exon 6 of 11

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

305

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00179

AC:

449

AN:

250734

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000282

Gnomad NFE exome

AF:

0.00303

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00243

AC:

2996

AN:

1234460

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

1500

AN XY:

626070

show subpopulations

African (AFR)

AF:

0.000377

AC:

AN:

29160

American (AMR)

AF:

0.00196

AC:

AN:

44428

Ashkenazi Jewish (ASJ)

AF:

0.000729

AC:

AN:

24690

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38484

South Asian (SAS)

AF:

0.0000735

AC:

AN:

81648

European-Finnish (FIN)

AF:

0.000342

AC:

AN:

52704

Middle Eastern (MID)

AF:

0.00170

AC:

AN:

5304

European-Non Finnish (NFE)

AF:

0.00296

AC:

2676

AN:

905130

Other (OTH)

AF:

0.00321

AC:

170

AN:

52912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

122

244

365

487

609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.00201

AC:

306

AN:

152296

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

159

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41564

American (AMR)

AF:

0.00248

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00326

AC:

222

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00209

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00176

AC:

213

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00362

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Glycogen storage disease IXb (3)

PHKB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.057

MetaRNN

Benign

0.023

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.9

PhyloP100

7.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.030

Polyphen

0.78

Vest4

0.65

MVP

0.92

MPC

0.19

ClinPred

0.034

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.61

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over