rs144486825

Positions:

• chr16-47503085-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 319333.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr16-47503085-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKB	NM_000293.3	c.400G>A	p.Asp134Asn	missense_variant	4/31	ENST00000323584.10
PHKB	NM_001363837.1	c.400G>A	p.Asp134Asn	missense_variant	4/31
PHKB	NM_001031835.3	c.379G>A	p.Asp127Asn	missense_variant	5/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKB	ENST00000323584.10	c.400G>A	p.Asp134Asn	missense_variant	4/31	1	NM_000293.3

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

GnomAD3 exomes AF: 0.00183 AC: 459 AN: 250894 Hom.: 3 AF XY: 0.00197 AC XY: 267 AN XY: 135606

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 SAS exome AF: 0.00213

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

Gnomad4 AFR exome AF: 0.00121

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00240

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

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00155 Hom.: 0

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycogen storage disease IXb Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PHKB: BS2 -

PHKB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.5	.;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.068	T;T;T;T;T
Sift4G	Uncertain	0.036	D;T;T;T;D
Polyphen		1.0, 1.0	.;D;.;D;.
Vest4		0.56, 0.57, 0.58
MVP		0.96
MPC		0.35
ClinPred		0.026	T
GERP RS		5.6
Varity_R		0.19
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs144486825; hg19: chr16-47536996;