rs34667348

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000293.3(PHKB):c.1969C>A(p.Gln657Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,604,956 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 15 hom. )

Consequence

PHKB
NM_000293.3 missense, splice_region

Scores

Splicing: ADA: 0.05761

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5O:1

Conservation

PhyloP100: 7.26

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026981533).

BP6

Variant 16-47650919-C-A is Benign according to our data. Variant chr16-47650919-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281127.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Uncertain_significance=5}. Variant chr16-47650919-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00282 (429/152312) while in subpopulation NFE AF= 0.00525 (357/68020). AF 95% confidence interval is 0.0048. There are 2 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PHKB	NM_000293.3 linkuse as main transcript	c.1969C>A	p.Gln657Lys	missense_variant, splice_region_variant	20/31	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1 linkuse as main transcript	c.1969C>A	p.Gln657Lys	missense_variant, splice_region_variant	20/31		NP_001350766.1
PHKB	NM_001031835.3 linkuse as main transcript	c.1948C>A	p.Gln650Lys	missense_variant, splice_region_variant	21/32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10 linkuse as main transcript	c.1969C>A	p.Gln657Lys	missense_variant, splice_region_variant	20/31	1	NM_000293.3	ENSP00000313504		Q93100-1

Frequencies

GnomAD3 genomes

AF:

0.00282

AC:

429

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00525

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00276

AC:

694

AN:

251224

Hom.:

AF XY:

0.00291

AC XY:

395

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00525

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00390

AC:

5669

AN:

1452644

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

2740

AN XY:

723288

show subpopulations

Gnomad4 AFR exome

AF:

0.000721

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000697

Gnomad4 FIN exome

AF:

0.00155

Gnomad4 NFE exome

AF:

0.00485

Gnomad4 OTH exome

AF:

0.00218

GnomAD4 genome

AF:

0.00282

AC:

429

AN:

152312

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00525

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00437

Hom.:

Bravo

AF:

0.00283

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00290

AC:

352

EpiCase

AF:

0.00387

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease IXb

Uncertain:2Benign:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 05, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2022	Reported as a variant of unclear significance in the heterozygous state in an individual with muscle glycogenosis and low phosphorylase kinase activity in whom a second PHKB variant was not identified (Burwinkle et al., 2003); Identified in a patient with myopathy and limb-girdle weakness with a second variant in PHKB, as well as variants in other genes but segregation information and in vitro functional studies were not included (Rotwein et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24082139, 28146470, 12825073, 29970176) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PHKB: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 31, 2022	BS1 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 13, 2023

Variant summary: PHKB c.1969C>A (p.Gln657Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0028 in 251224 control chromosomes, predominantly at a frequency of 0.0052 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PHKB causing Glycogen Phosphorylase Kinase Deficiency phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1969C>A has been reported in the literature in individuals affected with Glycogen Phosphorylase Kinase Deficiency or Limb girdle muscular dystrophies (Burwinkel_2003, Fichna_2018). These reports do not provide unequivocal conclusions about association of the variant with Glycogen Phosphorylase Kinase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17689125, 12825073, 29970176, 24082139, 28146470, 31214250). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=6) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

PHKB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2023

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

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

.;.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

1.7

.;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.76

MVP

0.91

MPC

0.63

ClinPred

0.017

GERP RS

4.8

Varity_R

0.61

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.058

dbscSNV1_RF

Benign

0.36

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