rs1556002344

Variant names:

• chrX-18924380-C-T
• rs1556002344
• NM_000292.3:c.1714+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000292.3(PHKA2):​c.1714+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PHKA2 NM_000292.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.79
• 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), Genomics England PanelApp, Ambry Genetics
• glycogen storage disease due to liver phosphorylase kinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18924380-C-T is Pathogenic according to our data. Variant chrX-18924380-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 526620.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000292.3. 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
	PHKA2	NM_000292.3	MANE Select	c.1714+1G>A		splice_donor intron	N/A	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.1714+1G>A		splice_donor intron	N/A	NP_001427734.1
	PHKA2	NM_001440800.1		c.1714+1G>A		splice_donor intron	N/A	NP_001427729.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	ENST00000379942.5	TSL:1 MANE Select	c.1714+1G>A		splice_donor intron	N/A	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.1714+1G>A		splice_donor intron	N/A	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.1714+1G>A		splice_donor intron	N/A	ENSP00000624789.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1097404 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362934

African (AFR) AF: 0.00 AC: 0 AN: 26375

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54121

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3830

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841694

Other (OTH) AF: 0.00 AC: 0 AN: 46055

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Glycogen storage disease IXa1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.8
GERP RS		5.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1556002344; hg19: chrX-18942498;