rs12918964

Variant names:

• chr16-47698565-C-T
• rs12918964
• NM_000293.3:c.3121C>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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:7
• Conservation: PhyloP100: 0.718
• Publications: 12 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 (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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKB	NM_000293.3	MANE Select	c.3121C>T	p.Arg1041Trp	missense	Exon 30 of 31	NP_000284.1
	PHKB	NM_001363837.1		c.3121C>T	p.Arg1041Trp	missense	Exon 30 of 31	NP_001350766.1
	PHKB	NM_001031835.3		c.3100C>T	p.Arg1034Trp	missense	Exon 31 of 32	NP_001027005.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKB	ENST00000323584.10	TSL:1 MANE Select	c.3121C>T	p.Arg1041Trp	missense	Exon 30 of 31	ENSP00000313504.5
	PHKB	ENST00000566044.5	TSL:1	c.3100C>T	p.Arg1034Trp	missense	Exon 31 of 32	ENSP00000456729.1
	PHKB	ENST00000940565.1		c.3199C>T	p.Arg1067Trp	missense	Exon 30 of 31	ENSP00000610624.1

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

GnomAD2 exomes AF: 0.00590 AC: 1455 AN: 246562 AF XY: 0.00594

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 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

African (AFR) AF: 0.00186 AC: 58 AN: 31118

American (AMR) AF: 0.00314 AC: 136 AN: 43290

Ashkenazi Jewish (ASJ) AF: 0.000122 AC: 3 AN: 24512

East Asian (EAS) AF: 0.0000823 AC: 3 AN: 36472

South Asian (SAS) AF: 0.000499 AC: 42 AN: 84158

European-Finnish (FIN) AF: 0.00458 AC: 227 AN: 49604

Middle Eastern (MID) AF: 0.00136 AC: 7 AN: 5146

European-Non Finnish (NFE) AF: 0.0133 AC: 13935 AN: 1046646

Other (OTH) AF: 0.0117 AC: 660 AN: 56222

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

African (AFR) AF: 0.00212 AC: 82 AN: 38768

American (AMR) AF: 0.00318 AC: 45 AN: 14130

Ashkenazi Jewish (ASJ) AF: 0.000593 AC: 2 AN: 3370

East Asian (EAS) AF: 0.00 AC: 0 AN: 4712

South Asian (SAS) AF: 0.000687 AC: 3 AN: 4364

European-Finnish (FIN) AF: 0.00532 AC: 39 AN: 7330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0128 AC: 846 AN: 65928

Other (OTH) AF: 0.00505 AC: 10 AN: 1982

Alfa AF: 0.00970 Hom.: 44

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease IXb (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.0019
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.72
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.22
Sift	Benign	0.041	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.24
MVP		0.78
MPC		0.28
ClinPred		0.035	T
GERP RS		3.0
Varity_R		0.047
gMVP		0.37
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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