chr16-47587662-G-C

Variant names:

• chr16-47587662-G-C
• rs56268318
• NM_000293.3:c.775-6G>C

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.000006794
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.61
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease IXb

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PHKB	NM_000293.3	c.775-6G>C		splice_region_variant, intron_variant	Intron 8 of 30	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1	c.775-6G>C		splice_region_variant, intron_variant	Intron 8 of 30		NP_001350766.1
PHKB	NM_001031835.3	c.754-6G>C		splice_region_variant, intron_variant	Intron 9 of 31		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10	c.775-6G>C		splice_region_variant, intron_variant	Intron 8 of 30	1	NM_000293.3	ENSP00000313504.5

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

GnomAD2 exomes AF: 0.0524 AC: 13140 AN: 250894 AF XY: 0.0477

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 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

African (AFR) AF: 0.324 AC: 10776 AN: 33288

American (AMR) AF: 0.0389 AC: 1737 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 798 AN: 26088

East Asian (EAS) AF: 0.00772 AC: 306 AN: 39648

South Asian (SAS) AF: 0.0267 AC: 2297 AN: 86110

European-Finnish (FIN) AF: 0.0156 AC: 830 AN: 53304

Middle Eastern (MID) AF: 0.0643 AC: 370 AN: 5758

European-Non Finnish (NFE) AF: 0.0413 AC: 45668 AN: 1106820

Other (OTH) AF: 0.0545 AC: 3281 AN: 60156

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

African (AFR) AF: 0.322 AC: 13350 AN: 41424

American (AMR) AF: 0.0621 AC: 948 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3468

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5184

South Asian (SAS) AF: 0.0285 AC: 137 AN: 4806

European-Finnish (FIN) AF: 0.0183 AC: 193 AN: 10572

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0412 AC: 2802 AN: 67996

Other (OTH) AF: 0.0981 AC: 207 AN: 2110

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 13, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.60
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000068
dbscSNV1_RF	Benign	0.0080
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs56268318; hg19: chr16-47621573;