16-30748488-C-T

Variant names:

• chr16-30748488-C-T
• rs534374752
• NM_000294.3:c.-21C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000294.3(PHKG2):​c.-21C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000401 in 249,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: PHKG2 NM_000294.3 splice_region
• Scores: Splicing: ADA: 0.0008847
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0200
• Publications: 0 publications found

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]

PHKG2 Gene-Disease associations (from GenCC):

• glycogen storage disease IXc

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• glycogen storage disease due to liver phosphorylase kinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260899 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000294.3. 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
	PHKG2	NM_000294.3	MANE Select	c.-21C>T		splice_region	Exon 1 of 10	NP_000285.1	P15735-1
	PHKG2	NM_000294.3	MANE Select	c.-21C>T		5_prime_UTR	Exon 1 of 10	NP_000285.1	P15735-1
	PHKG2	NM_001172432.2		c.-21C>T		splice_region	Exon 1 of 11	NP_001165903.1	P15735-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKG2	ENST00000563588.6	TSL:1 MANE Select	c.-21C>T		splice_region	Exon 1 of 10	ENSP00000455607.1	P15735-1
	PHKG2	ENST00000563588.6	TSL:1 MANE Select	c.-21C>T		5_prime_UTR	Exon 1 of 10	ENSP00000455607.1	P15735-1
	PHKG2	ENST00000328273.11	TSL:5	c.-21C>T		splice_region	Exon 1 of 10	ENSP00000329968.7	J3KNN3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000401 AC: 1 AN: 249570 Hom.: 0 Cov.: 0 AF XY: 0.00000767 AC XY: 1 AN XY: 130424

African (AFR) AF: 0.00 AC: 0 AN: 5700

American (AMR) AF: 0.00 AC: 0 AN: 9016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7878

East Asian (EAS) AF: 0.0000630 AC: 1 AN: 15880

South Asian (SAS) AF: 0.00 AC: 0 AN: 27490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1148

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 152202

Other (OTH) AF: 0.00 AC: 0 AN: 14920

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.020
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.058
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs534374752; hg19: chr16-30759809;