NM_000293.3:c.400G>A

Variant summary

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

The NM_000293.3(PHKB):​c.400G>A​(p.Asp134Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,591,420 control chromosomes in the GnomAD database, including 10 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 0.0018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 10 hom. )

Consequence

PHKB
NM_000293.3 missense

Scores

4
7
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 8.02

Publications

8 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)

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=0.026918948).
BP6
Variant 16-47503085-G-A is Benign according to our data. Variant chr16-47503085-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319333.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00181 (276/152322) while in subpopulation AMR AF = 0.00366 (56/15308). AF 95% confidence interval is 0.00289. There are 0 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PHKBNM_000293.3 linkc.400G>A p.Asp134Asn missense_variant Exon 4 of 31 ENST00000323584.10 NP_000284.1 Q93100-1
PHKBNM_001363837.1 linkc.400G>A p.Asp134Asn missense_variant Exon 4 of 31 NP_001350766.1
PHKBNM_001031835.3 linkc.379G>A p.Asp127Asn missense_variant Exon 5 of 32 NP_001027005.1 Q93100-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PHKBENST00000323584.10 linkc.400G>A p.Asp134Asn missense_variant Exon 4 of 31 1 NM_000293.3 ENSP00000313504.5 Q93100-1

Frequencies

GnomAD3 genomes
AF:
0.00181
AC:
275
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00133
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00366
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.00200
Gnomad OTH
AF:
0.00574
GnomAD2 exomes
AF:
0.00183
AC:
459
AN:
250894
AF XY:
0.00197
show subpopulations
Gnomad AFR exome
AF:
0.00148
Gnomad AMR exome
AF:
0.00313
Gnomad ASJ exome
AF:
0.000199
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00211
Gnomad OTH exome
AF:
0.00327
GnomAD4 exome
AF:
0.00162
AC:
2327
AN:
1439098
Hom.:
10
Cov.:
25
AF XY:
0.00170
AC XY:
1222
AN XY:
717556
show subpopulations
African (AFR)
AF:
0.00121
AC:
40
AN:
33028
American (AMR)
AF:
0.00309
AC:
138
AN:
44678
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25980
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39566
South Asian (SAS)
AF:
0.00211
AC:
181
AN:
85782
European-Finnish (FIN)
AF:
0.000244
AC:
13
AN:
53386
Middle Eastern (MID)
AF:
0.0126
AC:
72
AN:
5726
European-Non Finnish (NFE)
AF:
0.00159
AC:
1740
AN:
1091268
Other (OTH)
AF:
0.00240
AC:
143
AN:
59684
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
104
209
313
418
522
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
62
124
186
248
310
<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:
0.00181
AC:
276
AN:
152322
Hom.:
0
Cov.:
32
AF XY:
0.00180
AC XY:
134
AN XY:
74474
show subpopulations
African (AFR)
AF:
0.00132
AC:
55
AN:
41572
American (AMR)
AF:
0.00366
AC:
56
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00228
AC:
11
AN:
4826
European-Finnish (FIN)
AF:
0.0000942
AC:
1
AN:
10612
Middle Eastern (MID)
AF:
0.0170
AC:
5
AN:
294
European-Non Finnish (NFE)
AF:
0.00200
AC:
136
AN:
68028
Other (OTH)
AF:
0.00568
AC:
12
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
13
26
40
53
66
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<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:
0.00173
Hom.:
1
Bravo
AF:
0.00199
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.00227
AC:
10
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.00181
AC:
220
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.00289
EpiControl
AF:
0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Glycogen storage disease IXb Uncertain:2Benign:1
Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:3
Jun 04, 2018
GeneDx
Significance:Likely 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. -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PHKB: BS2 -

Dec 13, 2017
Mayo Clinic Laboratories, Mayo Clinic
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

PHKB-related disorder Benign:1
Feb 03, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.39
.;.;.;T;D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.027
T;T;T;T;T
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Uncertain
2.5
.;.;M;M;.
PhyloP100
8.0
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-2.3
N;N;N;N;N
REVEL
Uncertain
0.61
Sift
Benign
0.068
T;T;T;T;T
Sift4G
Uncertain
0.036
D;T;T;T;D
Polyphen
1.0, 1.0
.;D;.;D;.
Vest4
0.56, 0.57, 0.58
MVP
0.96
MPC
0.35
ClinPred
0.026
T
GERP RS
5.6
Varity_R
0.19
gMVP
0.56
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs144486825; hg19: chr16-47536996; API