16-30751234-G-C

Variant names:

• chr16-30751234-G-C
• rs538127151
• NM_000294.3:c.224G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000294.3(PHKG2):​c.224G>C​(p.Arg75Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PHKG2 NM_000294.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03

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]

ENSG00000260899 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity PHKG2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000294.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30829126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKG2	NM_000294.3	c.224G>C	p.Arg75Pro	missense_variant	Exon 3 of 10	ENST00000563588.6	NP_000285.1
PHKG2	NM_001172432.2	c.224G>C	p.Arg75Pro	missense_variant	Exon 3 of 11		NP_001165903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKG2	ENST00000563588.6	c.224G>C	p.Arg75Pro	missense_variant	Exon 3 of 10	1	NM_000294.3	ENSP00000455607.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460672 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.35	T;T;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.26	T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.042	B;.;P;.;.
Vest4		0.57
MutPred		0.67		Gain of glycosylation at R75 (P = 0.0263);Gain of glycosylation at R75 (P = 0.0263);Gain of glycosylation at R75 (P = 0.0263);Gain of glycosylation at R75 (P = 0.0263);Gain of glycosylation at R75 (P = 0.0263);
MVP		0.63
MPC		0.55
ClinPred		0.44	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.76

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: rs538127151; hg19: chr16-30762555;