chr16-47650919-C-T

Position:

• chr16-47650919-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000293.3(PHKB):​c.1969C>T​(p.Gln657Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,604,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PHKB NM_000293.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9873
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.26

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 Pathogenic. Variant got 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 16-47650919-C-T is Pathogenic according to our data. Variant chr16-47650919-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-47650919-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKB	NM_000293.3	c.1969C>T	p.Gln657Ter	stop_gained, splice_region_variant	20/31	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1	c.1969C>T	p.Gln657Ter	stop_gained, splice_region_variant	20/31		NP_001350766.1
PHKB	NM_001031835.3	c.1948C>T	p.Gln650Ter	stop_gained, splice_region_variant	21/32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10	c.1969C>T	p.Gln657Ter	stop_gained, splice_region_variant	20/31	1	NM_000293.3	ENSP00000313504

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251224 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 247 AN: 1452724 Hom.: 0 Cov.: 29 AF XY: 0.000174 AC XY: 126 AN XY: 723312

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000219 Hom.: 3

Bravo AF: 0.000166

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXb Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000013618). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 08, 2019	The PHKB c.1969C>T (p.Gln657Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Gln657Ter variant has been reported in a single study in which it was identified in a compound heterozygous state with a null variant on the second allele in two patients with glycogen storage disease due to phosphorylase kinase deficiency, one in combination with a frameshift variant and one with another stop-gained variant (Burwinkel et al. 1997). The p.Gln657Ter variant was reported in a heterozygous state in one of the unaffected parents. Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of PhK activity in patient erythrocytes demonstrated that each had 12-13% residual PhK activity compared to wild-type, with the heterozygous parent having 56% of normal activity (Burwinkel et al. 1997). Based on the evidence and the potential impact of stop-gained variants, the p.Gln657Ter variant is classified as likely pathogenic for phosphorylase kinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.The PHKB c.1969C>T (p.Gln657Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Gln657Ter variant has been reported in a single study in which it is found in a compound heterozygous state in two patients with glycogen storage disease due to phosphorylase kinase deficiency, one in combination with a frameshift variant and one with another stop-gained variant (Burwinkel et al. 1997). The p.Gln657Ter variant was reported in a heterozygous state in one of the unaffected parents. Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Analysis of PhK activity in patient erythrocytes demonstrated that each had 12-13% residual PhK activity compared to wild type, with the heterozygous parent having 56% of normal activity (Burwinkel et al. 1997). Based on the evidence and the potential impact of stop-gained variants, the p.Gln657Ter variant is classified as likely pathogenic for phosphorylase kinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 05, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Gln657*) in the PHKB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PHKB are known to be pathogenic (PMID: 9215682, 9326319). This variant is present in population databases (rs34667348, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 9215682). ClinVar contains an entry for this variant (Variation ID: 13618). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported (as Q656ter) in two individuals with glycogen storage disease type IX who also harbored a second variant in the PHKB gene (Burwinkel et al., 1997); This variant is associated with the following publications: (PMID: 25525159, 9215682, 34426522, 31589614) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.61
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34667348; hg19: chr16-47684830;