NM_000292.3:c.3027+48C>G

Variant names:

• chrX-18901437-G-C
• rs201339926
• NM_000292.3:c.3027+48C>G

Variant summary

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

The NM_000292.3(PHKA2):​c.3027+48C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 837,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: PHKA2 NM_000292.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

Genes affected

PHKA2 (HGNC:8926): (phosphorylase kinase regulatory subunit alpha 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, and the hepatic isoform is encoded by this gene. 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, which are 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 9A, also known as X-linked liver glycogenosis. Alternatively spliced transcript variants have been reported, but the full-length nature of these variants has not been determined.[provided by RefSeq, Feb 2010]

PHKA2 Gene-Disease associations (from GenCC):

• glycogen storage disease IXa1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3	c.3027+48C>G		intron_variant	Intron 27 of 32	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5	c.3027+48C>G		intron_variant	Intron 27 of 32	1	NM_000292.3	ENSP00000369274.4
PHKA2	ENST00000469645.5	n.511+48C>G		intron_variant	Intron 5 of 6	5
PHKA2	ENST00000473739.5	n.119+48C>G		intron_variant	Intron 1 of 5	3
PHKA2	ENST00000486231.2	n.296+48C>G		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111230 Hom.: 0 Cov.: 22

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182535 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 2 AN: 725832 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 212428

African (AFR) AF: 0.00 AC: 0 AN: 19117

American (AMR) AF: 0.00 AC: 0 AN: 34676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17081

East Asian (EAS) AF: 0.00 AC: 0 AN: 28392

South Asian (SAS) AF: 0.00 AC: 0 AN: 46862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3455

European-Non Finnish (NFE) AF: 0.00000398 AC: 2 AN: 502665

Other (OTH) AF: 0.00 AC: 0 AN: 33764

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111230 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33404

African (AFR) AF: 0.00 AC: 0 AN: 30593

American (AMR) AF: 0.00 AC: 0 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3527

South Asian (SAS) AF: 0.00 AC: 0 AN: 2597

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5995

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52980

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 7

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.5
DANN	Benign	0.45
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs201339926; hg19: chrX-18919555;