16-47461389-G-A

Position:

chr16-47461389-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PVS1_StrongBP6_Very_StrongBS2

The NM_000293.3(PHKB):c.39G>A(p.Trp13Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0016 in 1,613,112 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 22 hom. )

Consequence

PHKB
NM_000293.3 stop_gained

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.03

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:

ITFG1 (HGNC:30697): (integrin alpha FG-GAP repeat containing 1) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ITFG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.

BP6

Variant 16-47461389-G-A is Benign according to our data. Variant chr16-47461389-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 530957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-47461389-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PHKB	NM_000293.3 linkuse as main transcript	c.39G>A	p.Trp13Ter	stop_gained	1/31	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1 linkuse as main transcript	c.39G>A	p.Trp13Ter	stop_gained	1/31		NP_001350766.1
PHKB	NM_001031835.3 linkuse as main transcript	c.-95G>A		5_prime_UTR_variant	1/32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10 linkuse as main transcript	c.39G>A	p.Trp13Ter	stop_gained	1/31	1	NM_000293.3	ENSP00000313504		Q93100-1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00224

AC:

544

AN:

243322

Hom.:

AF XY:

0.00222

AC XY:

295

AN XY:

133076

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.0140

Gnomad NFE exome

AF:

0.00201

Gnomad OTH exome

AF:

0.00217

GnomAD4 exome

AF:

0.00155

AC:

2259

AN:

1460828

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1183

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0146

Gnomad4 NFE exome

AF:

0.00124

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.00209

AC:

319

AN:

152284

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0137

Gnomad4 NFE

AF:

0.00232

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00250

Hom.:

Bravo

AF:

0.000805

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00229

AC:

278

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease IXb

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2022

Variant summary: PHKB c.39G>A (p.Trp13X) results in a premature termination codon within the first exon of transcript NM_000293. An alternative transcript (NM_001031835) that is expressed in all tissues has a different initiation site downstream of this variant. The variant allele was found at a frequency of 0.0025 in 274676 control chromosomes (gnomAD), with 4 homozygotes. The variant occurs predominantly at a frequency of 0.014 within the Finnish subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in PHKB causing Glycogen Phosphorylase Kinase Deficiency (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

PHKB-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

PHKB: BS1:Supporting, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.88

MutationTaster

Benign

1.0

A;A;D;D

Vest4

0.17

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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