rs532057230

chr16-47669238-TGAA-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4_Supporting PP3 BP6_Very_Strong BS1 BS2

The NM_000293.3(PHKB):c.2459_2461del(p.Glu820del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,614,042 control chromosomes in the GnomAD database, including 45 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (40 hom.)
• Consequence: PHKB NM_000293.3 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.26

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 Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000293.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 16-47669238-TGAA-T is Benign according to our data. Variant chr16-47669238-TGAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 257176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0045 (686/152278) while in subpopulation NFE AF= 0.00272 (185/68014). AF 95% confidence interval is 0.0024. There are 5 homozygotes in gnomad4. There are 445 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKB	NM_000293.3	c.2459_2461del	p.Glu820del	inframe_deletion	26/31	ENST00000323584.10
PHKB	NM_001031835.3	c.2438_2440del	p.Glu813del	inframe_deletion	27/32
PHKB	NM_001363837.1	c.2459_2461del	p.Glu820del	inframe_deletion	26/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKB	ENST00000323584.10	c.2459_2461del	p.Glu820del	inframe_deletion	26/31	1	NM_000293.3

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152160 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00496 AC: 1247 AN: 251212 Hom.: 15 AF XY: 0.00483 AC XY: 656 AN XY: 135768

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0386

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00301 AC: 4394 AN: 1461764 Hom.: 40 AF XY: 0.00294 AC XY: 2138 AN XY: 727194

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0355

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00450 AC: 686 AN: 152278 Hom.: 5 Cov.: 32 AF XY: 0.00598 AC XY: 445 AN XY: 74464

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0421

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00251 Hom.: 1

Bravo AF: 0.00158

EpiCase AF: 0.00234

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PHKB: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Glycogen phosphorylase kinase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Glycogen storage disease IXb Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs532057230; hg19: chr16-47703149;