16-47515562-G-T

Position:

chr16-47515562-G-T

Variant summary

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

The ENST00000323584.10(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
ENST00000323584.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:12O:1

Conservation

PhyloP100: 8.28

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:

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ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PHKB	NM_000293.3 linkuse as main transcript	c.555G>T	p.Met185Ile	missense_variant	6/31	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1 linkuse as main transcript	c.555G>T	p.Met185Ile	missense_variant	6/31		NP_001350766.1
PHKB	NM_001031835.3 linkuse as main transcript	c.534G>T	p.Met178Ile	missense_variant	7/32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10 linkuse as main transcript	c.555G>T	p.Met185Ile	missense_variant	6/31	1	NM_000293.3	ENSP00000313504		Q93100-1

Frequencies

GnomAD3 genomes

AF:

0.00989

AC:

1505

AN:

152102

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0109

AC XY:

1473

AN XY:

135660

show subpopulations

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.:

AF XY:

0.0108

AC XY:

7309

AN XY:

678838

show subpopulations

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.:

Cov.:

AF XY:

0.00981

AC XY:

730

AN XY:

74418

show subpopulations

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.:

Bravo

AF:

0.00920

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0152

AC:

131

ExAC

AF:

0.0110

AC:

1339

Asia WGS

AF:

0.000869

AC:

AN:

3468

EpiCase

AF:

0.0149

EpiControl

AF:

0.0143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease IXb

Benign:5Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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. -
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 provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
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	May 30, 2017	- -

not specified

Benign:4

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	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

.;.;.;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.7

.;.;M;M

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.77

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

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

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