rs12918964

Positions:

• chr16-47698565-C-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.3121C>T​(p.Arg1041Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,518,908 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1041Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0074 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: PHKB NM_000293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.718

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 (MetaRNN=0.0072407722).
• BP6: Variant 16-47698565-C-T is Benign according to our data. Variant chr16-47698565-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 319360.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 = 0.00736 (1043/141740) while in subpopulation NFE AF= 0.0128 (846/65928). AF 95% confidence interval is 0.0121. There are 6 homozygotes in gnomad4. There are 470 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKB	NM_000293.3	c.3121C>T	p.Arg1041Trp	missense_variant	30/31	ENST00000323584.10
PHKB	NM_001363837.1	c.3121C>T	p.Arg1041Trp	missense_variant	30/31
PHKB	NM_001031835.3	c.3100C>T	p.Arg1034Trp	missense_variant	31/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKB	ENST00000323584.10	c.3121C>T	p.Arg1041Trp	missense_variant	30/31	1	NM_000293.3

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 1044 AN: 141718 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0179

Gnomad AMR AF: 0.00319

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000684

Gnomad FIN AF: 0.00532

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00509

GnomAD3 exomes AF: 0.00590 AC: 1455 AN: 246562 Hom.: 14 AF XY: 0.00594 AC XY: 794 AN XY: 133692

Gnomad AFR exome AF: 0.00205

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.000502

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000403

Gnomad FIN exome AF: 0.00451

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00483

GnomAD4 exome AF: 0.0109 AC: 15071 AN: 1377168 Hom.: 105 Cov.: 31 AF XY: 0.0105 AC XY: 7206 AN XY: 687628

Gnomad4 AFR exome AF: 0.00186

Gnomad4 AMR exome AF: 0.00314

Gnomad4 ASJ exome AF: 0.000122

Gnomad4 EAS exome AF: 0.0000823

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00458

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00736 AC: 1043 AN: 141740 Hom.: 6 Cov.: 32 AF XY: 0.00688 AC XY: 470 AN XY: 68314

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00318

Gnomad4 ASJ AF: 0.000593

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000687

Gnomad4 FIN AF: 0.00532

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00505

Alfa AF: 0.00985 Hom.: 21

Bravo AF: 0.00674

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.00573 AC: 695

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.0101

EpiControl AF: 0.00946

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXb Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PHKB: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.0019
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N;N;N
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.99	D;.;P
Vest4		0.24
MVP		0.78
MPC		0.28
ClinPred		0.035	T
GERP RS		3.0
Varity_R		0.047
gMVP		0.37

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: rs12918964; hg19: chr16-47732476; COSMIC: COSV54529126;