rs151155518

chr16-47511759-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000293.3(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 NM_000293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.19

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKB	NM_000293.3	c.500A>G	p.Tyr167Cys	missense_variant	5/31	ENST00000323584.10
PHKB	NM_001363837.1	c.500A>G	p.Tyr167Cys	missense_variant	5/31
PHKB	NM_001031835.3	c.479A>G	p.Tyr160Cys	missense_variant	6/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKB	ENST00000323584.10	c.500A>G	p.Tyr167Cys	missense_variant	5/31	1	NM_000293.3

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152170 Hom.: 1 Cov.: 32

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.: 10 AF XY: 0.00455 AC XY: 618 AN XY: 135854

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.: 17 Cov.: 25 AF XY: 0.00455 AC XY: 3215 AN XY: 706808

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.: 1 Cov.: 32 AF XY: 0.00393 AC XY: 293 AN XY: 74470

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.: 2

Bravo AF: 0.00325

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00500 AC: 43

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

Submissions by phenotype

Glycogen storage disease IXb Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	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	Mar 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, criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
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	T
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

Other links and lift over

dbSNP: rs151155518; hg19: chr16-47545670;