rs144486825

Variant names:

• chr16-47503085-G-A
• rs144486825
• NM_000293.3:c.400G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-47503085-G-A
• chr16-47503085-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000293.3(PHKB):​c.400G>A​(p.Asp134Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,591,420 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: PHKB NM_000293.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 8.02
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026918948).
• BP6: Variant 16-47503085-G-A is Benign according to our data. Variant chr16-47503085-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319333.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00181 (276/152322) while in subpopulation AMR AF = 0.00366 (56/15308). AF 95% confidence interval is 0.00289. There are 0 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.400G>A	p.Asp134Asn	missense	Exon 4 of 31	NP_000284.1	Q93100-1
	PHKB	NM_001363837.1		c.400G>A	p.Asp134Asn	missense	Exon 4 of 31	NP_001350766.1	Q93100-3
	PHKB	NM_001031835.3		c.379G>A	p.Asp127Asn	missense	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.400G>A	p.Asp134Asn	missense	Exon 4 of 31	ENSP00000313504.5	Q93100-1
	PHKB	ENST00000566044.5	TSL:1	c.379G>A	p.Asp127Asn	missense	Exon 5 of 32	ENSP00000456729.1	Q93100-4
	PHKB	ENST00000567402.5	TSL:1	n.415G>A		non_coding_transcript_exon	Exon 4 of 11

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00183 AC: 459 AN: 250894 AF XY: 0.00197

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00211

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00162 AC: 2327 AN: 1439098 Hom.: 10 Cov.: 25 AF XY: 0.00170 AC XY: 1222 AN XY: 717556

African (AFR) AF: 0.00121 AC: 40 AN: 33028

American (AMR) AF: 0.00309 AC: 138 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00211 AC: 181 AN: 85782

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53386

Middle Eastern (MID) AF: 0.0126 AC: 72 AN: 5726

European-Non Finnish (NFE) AF: 0.00159 AC: 1740 AN: 1091268

Other (OTH) AF: 0.00240 AC: 143 AN: 59684

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74474

African (AFR) AF: 0.00132 AC: 55 AN: 41572

American (AMR) AF: 0.00366 AC: 56 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68028

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00173 Hom.: 1

Bravo AF: 0.00199

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00181 AC: 220

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00273

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.027	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.61
Sift	Benign	0.068	T
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.96
MPC		0.35
ClinPred		0.026	T
GERP RS		5.6
Varity_R		0.19
gMVP		0.56
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144486825; hg19: chr16-47536996;