16-30748833-G-A

Position:

• chr16-30748833-G-A

Variant summary

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

The ENST00000563588.6(PHKG2):​c.13G>A​(p.Val5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,399,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PHKG2 ENST00000563588.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

Genes affected

PHKG2 (HGNC:8931): (phosphorylase kinase catalytic subunit gamma 2) 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, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, and the hepatic isoform is encoded by this gene. 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 9C, also known as autosomal liver glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

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=0.14575595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKG2	NM_000294.3	c.13G>A	p.Val5Met	missense_variant	2/10	ENST00000563588.6	NP_000285.1
PHKG2	NM_001172432.2	c.13G>A	p.Val5Met	missense_variant	2/11		NP_001165903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKG2	ENST00000563588.6	c.13G>A	p.Val5Met	missense_variant	2/10	1	NM_000294.3	ENSP00000455607	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1399828 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000378

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.13G>A (p.V5M) alteration is located in exon 2 (coding exon 1) of the PHKG2 gene. This alteration results from a G to A substitution at nucleotide position 13, causing the valine (V) at amino acid position 5 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.30	N;.;N;.;.
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.40	N;N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.055	T;T;D;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.49	P;.;B;.;.
Vest4		0.14
MutPred		0.24		Gain of disorder (P = 0.0705);Gain of disorder (P = 0.0705);Gain of disorder (P = 0.0705);Gain of disorder (P = 0.0705);Gain of disorder (P = 0.0705);
MVP		0.73
MPC		0.85
ClinPred		0.75	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.33

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: rs1166994744; hg19: chr16-30760154;