rs56257827

chr16-47515562-G-T

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.555G>T(p.Met185Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,504,410 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (17 hom., cov: 32)
  • Exomes 𝑓: 0.011 (129 hom.)
• Consequence: PHKB NM_000293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11 O:1
• Conservation: PhyloP100: 8.28

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=0.009557545).
• BP6: Variant 16-47515562-G-T is Benign according to our data. Variant chr16-47515562-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 198067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-47515562-G-T is described in Lovd as [Benign]. Variant chr16-47515562-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00989 (1505/152220) while in subpopulation NFE AF= 0.013 (886/68002). AF 95% confidence interval is 0.0123. There are 17 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKB	NM_000293.3	c.555G>T	p.Met185Ile	missense_variant	6/31	ENST00000323584.10
PHKB	NM_001363837.1	c.555G>T	p.Met185Ile	missense_variant	6/31
PHKB	NM_001031835.3	c.534G>T	p.Met178Ile	missense_variant	7/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKB	ENST00000323584.10	c.555G>T	p.Met185Ile	missense_variant	6/31	1	NM_000293.3

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1505 AN: 152102 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0112 AC: 2799 AN: 250950 Hom.: 33 AF XY: 0.0109 AC XY: 1473 AN XY: 135660

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.0629

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0110 AC: 14830 AN: 1352190 Hom.: 129 Cov.: 22 AF XY: 0.0108 AC XY: 7309 AN XY: 678838

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.00523

Gnomad4 ASJ exome AF: 0.0628

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00142

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.00989 AC: 1505 AN: 152220 Hom.: 17 Cov.: 32 AF XY: 0.00981 AC XY: 730 AN XY: 74418

Gnomad4 AFR AF: 0.00234

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.0628

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0146 Hom.: 45

Bravo AF: 0.00920

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0152 AC: 131

ExAC AF: 0.0110 AC: 1339

Asia WGS AF: 0.000869 AC: 3 AN: 3468

EpiCase AF: 0.0149

EpiControl AF: 0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXb Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 21, 2021	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Met185Ile in PHKB has been identified in an individual with liver glycogenosis but no other variant in the gene was identified (PMID: 17689125). This variant has also been identified in >1% of European (non-Finnish) chromosomes and 17 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive liver glycogenosis. -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2017	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. -
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	Eurofins Ntd Llc (ga)	May 26, 2015	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PHKB: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
MetaRNN	Benign	0.0096	T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D;D;D;D
Sift	Benign	0.043	D;D;D;D
Sift4G	Uncertain	0.054	T;D;D;D
Polyphen		0.98, 0.73	.;D;.;P
Vest4		0.70, 0.34, 0.38
MutPred		0.85		.;.;Gain of catalytic residue at S187 (P = 0.0981);Gain of catalytic residue at S187 (P = 0.0981);
MPC		0.40
ClinPred		0.012	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.84

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: rs56257827; hg19: chr16-47549473;