rs17738933

Variant names:

• chr16-47503003-T-C
• rs17738933
• NM_000293.3:c.318T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000293.3(PHKB):​c.318T>C​(p.Asp106Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,611,428 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 32)
  • Exomes 𝑓: 0.018 (303 hom.)
• Consequence: PHKB NM_000293.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.80
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-47503003-T-C is Benign according to our data. Variant chr16-47503003-T-C is described in ClinVar as Benign. ClinVar VariationId is 257178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0132 (2014/152316) while in subpopulation NFE AF = 0.0203 (1381/68030). AF 95% confidence interval is 0.0194. There are 32 homozygotes in GnomAd4. There are 936 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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.318T>C	p.Asp106Asp	synonymous	Exon 4 of 31	NP_000284.1	Q93100-1
	PHKB	NM_001363837.1		c.318T>C	p.Asp106Asp	synonymous	Exon 4 of 31	NP_001350766.1	Q93100-3
	PHKB	NM_001031835.3		c.297T>C	p.Asp99Asp	synonymous	Exon 5 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.318T>C	p.Asp106Asp	synonymous	Exon 4 of 31	ENSP00000313504.5	Q93100-1
	PHKB	ENST00000566044.5	TSL:1	c.297T>C	p.Asp99Asp	synonymous	Exon 5 of 32	ENSP00000456729.1	Q93100-4
	PHKB	ENST00000567402.5	TSL:1	n.333T>C		non_coding_transcript_exon	Exon 4 of 11

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2018 AN: 152198 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0146 AC: 3665 AN: 251280 AF XY: 0.0140

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00605

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0181 AC: 26405 AN: 1459112 Hom.: 303 Cov.: 29 AF XY: 0.0176 AC XY: 12782 AN XY: 726130

African (AFR) AF: 0.00215 AC: 72 AN: 33426

American (AMR) AF: 0.00387 AC: 173 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00681 AC: 178 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39686

South Asian (SAS) AF: 0.00216 AC: 186 AN: 86194

European-Finnish (FIN) AF: 0.0345 AC: 1840 AN: 53406

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5766

European-Non Finnish (NFE) AF: 0.0208 AC: 23075 AN: 1109480

Other (OTH) AF: 0.0141 AC: 851 AN: 60310

GnomAD4 genome AF: 0.0132 AC: 2014 AN: 152316 Hom.: 32 Cov.: 32 AF XY: 0.0126 AC XY: 936 AN XY: 74472

African (AFR) AF: 0.00330 AC: 137 AN: 41566

American (AMR) AF: 0.00346 AC: 53 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0343 AC: 364 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0203 AC: 1381 AN: 68030

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0163 Hom.: 37

Bravo AF: 0.0113

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.4
DANN	Benign	0.77
PhyloP100		1.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs17738933; hg19: chr16-47536914;