rs151155518

Positions:

chr16-47511759-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000323584.10(PHKB):c.500A>G(p.Tyr167Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00449 in 1,567,224 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 17 hom. )

Consequence

PHKB
ENST00000323584.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.19

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012756854).

BP6

Variant 16-47511759-A-G is Benign according to our data. Variant chr16-47511759-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 319336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-47511759-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00382 (581/152288) while in subpopulation NFE AF= 0.00567 (386/68020). AF 95% confidence interval is 0.00521. There are 1 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PHKB	NM_000293.3 linkuse as main transcript	c.500A>G	p.Tyr167Cys	missense_variant	5/31	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1 linkuse as main transcript	c.500A>G	p.Tyr167Cys	missense_variant	5/31		NP_001350766.1
PHKB	NM_001031835.3 linkuse as main transcript	c.479A>G	p.Tyr160Cys	missense_variant	6/32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10 linkuse as main transcript	c.500A>G	p.Tyr167Cys	missense_variant	5/31	1	NM_000293.3	ENSP00000313504		Q93100-1

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

581

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0115

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00567

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00460

AC:

1157

AN:

251370

Hom.:

AF XY:

0.00455

AC XY:

618

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0139

Gnomad NFE exome

AF:

0.00661

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00457

AC:

6462

AN:

1414936

Hom.:

Cov.:

AF XY:

0.00455

AC XY:

3215

AN XY:

706808

show subpopulations

Gnomad4 AFR exome

AF:

0.000676

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.0000760

Gnomad4 SAS exome

AF:

0.000375

Gnomad4 FIN exome

AF:

0.0120

Gnomad4 NFE exome

AF:

0.00508

Gnomad4 OTH exome

AF:

0.00401

GnomAD4 genome

AF:

0.00382

AC:

581

AN:

152288

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

293

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0115

Gnomad4 NFE

AF:

0.00567

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00477

Hom.:

Bravo

AF:

0.00325

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00483

AC:

586

EpiCase

AF:

0.00403

EpiControl

AF:

0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease IXb

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: PHKB c.500A>G (p.Tyr167Cys) results in a non-conservative amino acid change located in the GH15-like domain (IPR011613) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 251370 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 4-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 benign. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PHKB: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -

PHKB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2020

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

0.15

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

.;.;.;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D;D

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.5

.;.;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.8

D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

1.0, 1.0

.;D;.;D

Vest4

0.96, 0.96

MVP

0.98

MPC

0.61

ClinPred

0.037

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.65

gMVP

0.85

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

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