rs17738933

Positions:

• chr16-47503003-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000293.3(PHKB):​c.318T>C​(p.Asp106=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,611,428 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 32)
  • Exomes 𝑓: 0.018 (303 hom.)
• Consequence: PHKB NM_000293.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.80

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-47503003-T-C is Benign according to our data. Variant chr16-47503003-T-C is described in ClinVar as [Benign]. Clinvar id is 257178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2014/152316) while in subpopulation NFE AF= 0.0203 (1381/68030). AF 95% confidence interval is 0.0194. There are 32 homozygotes in gnomad4. There are 936 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKB	NM_000293.3	c.318T>C	p.Asp106=	synonymous_variant	4/31	ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1	c.318T>C	p.Asp106=	synonymous_variant	4/31		NP_001350766.1
PHKB	NM_001031835.3	c.297T>C	p.Asp99=	synonymous_variant	5/32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10	c.318T>C	p.Asp106=	synonymous_variant	4/31	1	NM_000293.3	ENSP00000313504

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2018 AN: 152198 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0146 AC: 3665 AN: 251280 Hom.: 61 AF XY: 0.0140 AC XY: 1903 AN XY: 135810

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0181 AC: 26405 AN: 1459112 Hom.: 303 Cov.: 29 AF XY: 0.0176 AC XY: 12782 AN XY: 726130

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.00681

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.0345

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0132 AC: 2014 AN: 152316 Hom.: 32 Cov.: 32 AF XY: 0.0126 AC XY: 936 AN XY: 74472

Gnomad4 AFR AF: 0.00330

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0343

Gnomad4 NFE AF: 0.0203

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0166 Hom.: 31

Bravo AF: 0.0113

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXb Benign:3

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	Oct 09, 2023	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 22, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.4
DANN	Benign	0.77
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs17738933; hg19: chr16-47536914;