16-47461364-C-T

Variant names:

• chr16-47461364-C-T
• rs778015344
• NM_000293.3:c.14C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000293.3(PHKB):​c.14C>T​(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PHKB NM_000293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16410032).

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.14C>T	p.Ala5Val	missense	Exon 1 of 31	NP_000284.1	Q93100-1
	PHKB	NM_001363837.1		c.14C>T	p.Ala5Val	missense	Exon 1 of 31	NP_001350766.1	Q93100-3
	PHKB	NM_001031835.3		c.-120C>T		5_prime_UTR	Exon 1 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.14C>T	p.Ala5Val	missense	Exon 1 of 31	ENSP00000313504.5	Q93100-1
	PHKB	ENST00000566044.5	TSL:1	c.-120C>T		5_prime_UTR	Exon 1 of 32	ENSP00000456729.1	Q93100-4
	PHKB	ENST00000567402.5	TSL:1	n.29C>T		non_coding_transcript_exon	Exon 1 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000846 AC: 2 AN: 236500 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000964

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458644 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725604

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.0000224 AC: 1 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111168

Other (OTH) AF: 0.0000166 AC: 1 AN: 60228

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disease IXb (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.34	T
Polyphen		0.029	B
Vest4		0.33
MutPred		0.30		Gain of sheet (P = 0.0125)
MVP		0.80
MPC		0.12
ClinPred		0.14	T
GERP RS		0.99
PromoterAI		-0.051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.036
gMVP		0.39
Mutation Taster		=293/7	polymorphism

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: rs778015344; hg19: chr16-47495275; COSMIC: COSV54519851; COSMIC: COSV54519851;