rs117536391

Positions:

• chr16-47596544-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000293.3(PHKB):​c.1363+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,610,608 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 32)
  • Exomes 𝑓: 0.017 (305 hom.)
• Consequence: PHKB NM_000293.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.326

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 16-47596544-G-T is Benign according to our data. Variant chr16-47596544-G-T is described in ClinVar as [Benign]. Clinvar id is 257171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0124 (1887/152262) while in subpopulation SAS AF= 0.0328 (158/4822). AF 95% confidence interval is 0.0286. There are 19 homozygotes in gnomad4. There are 942 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKB	NM_000293.3	c.1363+13G>T		intron_variant		ENST00000323584.10	NP_000284.1
PHKB	NM_001363837.1	c.1363+13G>T		intron_variant			NP_001350766.1
PHKB	NM_001031835.3	c.1342+13G>T		intron_variant			NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10	c.1363+13G>T		intron_variant		1	NM_000293.3	ENSP00000313504.5

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152144 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.0165 AC: 4153 AN: 250936 Hom.: 69 AF XY: 0.0185 AC XY: 2508 AN XY: 135644

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00627

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0366

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0168 AC: 24539 AN: 1458346 Hom.: 305 Cov.: 29 AF XY: 0.0177 AC XY: 12868 AN XY: 725666

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.00630

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0124 AC: 1887 AN: 152262 Hom.: 19 Cov.: 32 AF XY: 0.0127 AC XY: 942 AN XY: 74446

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0328

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0167 Hom.: 7

Bravo AF: 0.0106

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Mar 17, 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 13, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.8
DANN	Benign	0.75

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: rs117536391; hg19: chr16-47630455;