16-47461373-C-T

Position:

• chr16-47461373-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001031835.3(PHKB):​c.-111C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,612,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PHKB NM_001031835.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.171

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 (HGNC:):

ITFG1 (HGNC:30697): (integrin alpha FG-GAP repeat containing 1) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07326278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKB	NM_000293.3	c.23C>T	p.Thr8Met	missense_variant	1/31	ENST00000323584.10	NP_000284.1
PHKB	NM_001031835.3	c.-111C>T		5_prime_UTR_premature_start_codon_gain_variant	1/32		NP_001027005.1
PHKB	NM_001363837.1	c.23C>T	p.Thr8Met	missense_variant	1/31		NP_001350766.1
PHKB	NM_001031835.3	c.-111C>T		5_prime_UTR_variant	1/32		NP_001027005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKB	ENST00000323584.10	c.23C>T	p.Thr8Met	missense_variant	1/31	1	NM_000293.3	ENSP00000313504.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000333 AC: 8 AN: 240264 Hom.: 0 AF XY: 0.0000379 AC XY: 5 AN XY: 131880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000877

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000283

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1459968 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 726326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 07, 2023

BP4, PM2_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	4.8
DANN	Benign	0.83
DEOGEN2	Benign	0.031	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.59	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.69	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.14
Sift	Benign	0.27	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0	.;B
Vest4		0.17
MutPred		0.36		Gain of helix (P = 0.005);Gain of helix (P = 0.005);
MVP		0.75
MPC		0.12
ClinPred		0.052	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs768309023; hg19: chr16-47495284;