16-47669246-A-T

Variant names:

• chr16-47669246-A-T
• rs9934849
• NM_000293.3:c.2459A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000293.3(PHKB):​c.2459A>T​(p.Glu820Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00076 in 1,613,934 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: PHKB NM_000293.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.22
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 16-47669246-A-T is Benign according to our data. Variant chr16-47669246-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00422 (642/152134) while in subpopulation AFR AF = 0.0147 (611/41544). AF 95% confidence interval is 0.0137. There are 6 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 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKB	NM_000293.3	MANE Select	c.2459A>T	p.Glu820Val	missense	Exon 26 of 31	NP_000284.1	Q93100-1
	PHKB	NM_001363837.1		c.2459A>T	p.Glu820Val	missense	Exon 26 of 31	NP_001350766.1	Q93100-3
	PHKB	NM_001031835.3		c.2438A>T	p.Glu813Val	missense	Exon 27 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.2459A>T	p.Glu820Val	missense	Exon 26 of 31	ENSP00000313504.5	Q93100-1
	PHKB	ENST00000566044.5	TSL:1	c.2438A>T	p.Glu813Val	missense	Exon 27 of 32	ENSP00000456729.1	Q93100-4
	PHKB	ENST00000940565.1		c.2537A>T	p.Glu846Val	missense	Exon 26 of 31	ENSP00000610624.1

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 641 AN: 152016 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00123 AC: 309 AN: 251246 AF XY: 0.000862

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000400 AC: 585 AN: 1461800 Hom.: 3 Cov.: 32 AF XY: 0.000315 AC XY: 229 AN XY: 727206

African (AFR) AF: 0.0135 AC: 452 AN: 33474

American (AMR) AF: 0.000984 AC: 44 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111960

Other (OTH) AF: 0.000795 AC: 48 AN: 60390

GnomAD4 genome AF: 0.00422 AC: 642 AN: 152134 Hom.: 6 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74350

African (AFR) AF: 0.0147 AC: 611 AN: 41544

American (AMR) AF: 0.00137 AC: 21 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00179 Hom.: 2

Bravo AF: 0.00453

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00158 AC: 192

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.51
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	0.99	T
Polyphen		0.079	B
Vest4		0.36
MVP		0.85
MPC		0.16
ClinPred		0.072	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.54
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9934849; hg19: chr16-47703157;