rs56268318

chr16-47587662-G-C

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.775-6G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0522 in 1,607,860 control chromosomes in the GnomAD database, including 5,304 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2299 hom., cov: 32)
  • Exomes 𝑓: 0.045 (3005 hom.)
• Consequence: PHKB NM_000293.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000006794
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.61

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 (BayesDel_noAF=-0.83).
• BP6: Variant 16-47587662-G-C is Benign according to our data. Variant chr16-47587662-G-C is described in ClinVar as [Benign]. Clinvar id is 257179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-47587662-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKB	NM_000293.3	c.775-6G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000323584.10
PHKB	NM_001031835.3	c.754-6G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
PHKB	NM_001363837.1	c.775-6G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKB	ENST00000323584.10	c.775-6G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000293.3

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17776 AN: 151912 Hom.: 2278 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.0291

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0412

Gnomad OTH AF: 0.0982

GnomAD3 exomes AF: 0.0524 AC: 13140 AN: 250894 Hom.: 970 AF XY: 0.0477 AC XY: 6465 AN XY: 135596

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0141

Gnomad SAS exome AF: 0.0275

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0410

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0454 AC: 66063 AN: 1455830 Hom.: 3005 Cov.: 28 AF XY: 0.0440 AC XY: 31900 AN XY: 724696

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0306

Gnomad4 EAS exome AF: 0.00772

Gnomad4 SAS exome AF: 0.0267

Gnomad4 FIN exome AF: 0.0156

Gnomad4 NFE exome AF: 0.0413

Gnomad4 OTH exome AF: 0.0545

GnomAD4 genome AF: 0.117 AC: 17840 AN: 152030 Hom.: 2299 Cov.: 32 AF XY: 0.114 AC XY: 8457 AN XY: 74308

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.0621

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.0285

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0412

Gnomad4 OTH AF: 0.0981

Alfa AF: 0.0611 Hom.: 202

Bravo AF: 0.129

Asia WGS AF: 0.0390 AC: 137 AN: 3478

EpiCase AF: 0.0480

EpiControl AF: 0.0470

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 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. -

Glycogen storage disease IXb Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

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
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.5
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000068
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.0		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: rs56268318; hg19: chr16-47621573;