rs151155518

Variant names:

• chr16-47511759-A-G
• rs151155518
• NM_000293.3:c.500A>G

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.500A>G​(p.Tyr167Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00449 in 1,567,224 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (17 hom.)
• Consequence: PHKB NM_000293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.19
• Publications: 13 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, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012756854).
• BP6: Variant 16-47511759-A-G is Benign according to our data. Variant chr16-47511759-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319336.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 = 0.00382 (581/152288) while in subpopulation NFE AF = 0.00567 (386/68020). AF 95% confidence interval is 0.00521. There are 1 homozygotes in GnomAd4. There are 293 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKB	NM_000293.3	MANE Select	c.500A>G	p.Tyr167Cys	missense	Exon 5 of 31	NP_000284.1	Q93100-1
	PHKB	NM_001363837.1		c.500A>G	p.Tyr167Cys	missense	Exon 5 of 31	NP_001350766.1	Q93100-3
	PHKB	NM_001031835.3		c.479A>G	p.Tyr160Cys	missense	Exon 6 of 32	NP_001027005.1	Q93100-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKB	ENST00000323584.10	TSL:1 MANE Select	c.500A>G	p.Tyr167Cys	missense	Exon 5 of 31	ENSP00000313504.5	Q93100-1
	PHKB	ENST00000566044.5	TSL:1	c.479A>G	p.Tyr160Cys	missense	Exon 6 of 32	ENSP00000456729.1	Q93100-4
	PHKB	ENST00000567402.5	TSL:1	n.515A>G		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00567

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00460 AC: 1157 AN: 251370 AF XY: 0.00455

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00457 AC: 6462 AN: 1414936 Hom.: 17 Cov.: 25 AF XY: 0.00455 AC XY: 3215 AN XY: 706808

African (AFR) AF: 0.000676 AC: 22 AN: 32528

American (AMR) AF: 0.00159 AC: 71 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25894

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39458

South Asian (SAS) AF: 0.000375 AC: 32 AN: 85298

European-Finnish (FIN) AF: 0.0120 AC: 641 AN: 53376

Middle Eastern (MID) AF: 0.00352 AC: 20 AN: 5678

European-Non Finnish (NFE) AF: 0.00508 AC: 5433 AN: 1069248

Other (OTH) AF: 0.00401 AC: 236 AN: 58786

GnomAD4 genome AF: 0.00382 AC: 581 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00393 AC XY: 293 AN XY: 74470

African (AFR) AF: 0.000650 AC: 27 AN: 41562

American (AMR) AF: 0.00222 AC: 34 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.0115 AC: 122 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00567 AC: 386 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00503 Hom.: 5

Bravo AF: 0.00325

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00483 AC: 586

EpiCase AF: 0.00403

EpiControl AF: 0.00427

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease IXb (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	PHKB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.98
MPC		0.61
ClinPred		0.037	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.85
Mutation Taster		=31/69	disease causing

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: rs151155518; hg19: chr16-47545670; COSMIC: COSV106100671; COSMIC: COSV106100671;