rs16945474

Positions:

• chr16-47663707-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000293.3(PHKB):​c.2309A>G​(p.Tyr770Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,611,382 control chromosomes in the GnomAD database, including 2,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (610 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1580 hom.)
• Consequence: PHKB NM_000293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.19

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=0.0038224757).
• BP6: Variant 16-47663707-A-G is Benign according to our data. Variant chr16-47663707-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-47663707-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKB	NM_000293.3	c.2309A>G	p.Tyr770Cys	missense_variant	24/31	ENST00000323584.10
PHKB	NM_001363837.1	c.2309A>G	p.Tyr770Cys	missense_variant	24/31
PHKB	NM_001031835.3	c.2288A>G	p.Tyr763Cys	missense_variant	25/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKB	ENST00000323584.10	c.2309A>G	p.Tyr770Cys	missense_variant	24/31	1	NM_000293.3

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10578 AN: 152174 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.0138

Gnomad SAS AF: 0.0283

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0654

GnomAD3 exomes AF: 0.0404 AC: 10154 AN: 251204 Hom.: 307 AF XY: 0.0393 AC XY: 5338 AN XY: 135774

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.0280

Gnomad ASJ exome AF: 0.0287

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.0273

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0411 AC: 60021 AN: 1459090 Hom.: 1580 Cov.: 29 AF XY: 0.0405 AC XY: 29427 AN XY: 726024

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.0295

Gnomad4 ASJ exome AF: 0.0297

Gnomad4 EAS exome AF: 0.00807

Gnomad4 SAS exome AF: 0.0262

Gnomad4 FIN exome AF: 0.0156

Gnomad4 NFE exome AF: 0.0417

Gnomad4 OTH exome AF: 0.0454

GnomAD4 genome AF: 0.0695 AC: 10583 AN: 152292 Hom.: 610 Cov.: 32 AF XY: 0.0674 AC XY: 5019 AN XY: 74470

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.0439

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.0277

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.0411

Gnomad4 OTH AF: 0.0652

Alfa AF: 0.0473 Hom.: 414

Bravo AF: 0.0759

TwinsUK AF: 0.0388 AC: 144

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.152 AC: 671

ESP6500EA AF: 0.0436 AC: 375

ExAC AF: 0.0423 AC: 5138

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.0479

EpiControl AF: 0.0469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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	PreventionGenetics, part of Exact Sciences	-	- -

Glycogen storage disease IXb Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	4.0e-11	P;P;P;P
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	D;D;D;.
Sift	Benign	0.11	T;T;T;.
Sift4G	Benign	0.097	T;T;T;T
Polyphen		0.91	P;.;B;.
Vest4		0.81
MPC		0.56
ClinPred		0.043	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16945474; hg19: chr16-47697618; COSMIC: COSV54520158; COSMIC: COSV54520158;