rs140662042

Variant names:

• chrX-18941678-G-A
• rs140662042
• NM_000292.3:c.718-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000292.3(PHKA2):​c.718-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0151 in 1,157,524 control chromosomes in the GnomAD database, including 121 homozygotes. There are 4,958 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (8 hom., 352 hem., cov: 23)
  • Exomes 𝑓: 0.016 (113 hom. 4606 hem.)
• Consequence: PHKA2 NM_000292.3 splice_region, intron
• Scores: Splicing: ADA: 0.01200
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.62
• Publications: 2 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant X-18941678-G-A is Benign according to our data. Variant chrX-18941678-G-A is described in ClinVar as Benign. ClinVar VariationId is 255778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1284/113254) while in subpopulation NFE AF = 0.0198 (1055/53403). AF 95% confidence interval is 0.0188. There are 8 homozygotes in GnomAd4. There are 352 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 XL,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	NM_000292.3	MANE Select	c.718-3C>T		splice_region intron	N/A	NP_000283.1
	PHKA2	NM_001440805.1		c.718-3C>T		splice_region intron	N/A	NP_001427734.1
	PHKA2	NM_001440800.1		c.718-3C>T		splice_region intron	N/A	NP_001427729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	ENST00000379942.5	TSL:1 MANE Select	c.718-3C>T		splice_region intron	N/A	ENSP00000369274.4

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1285 AN: 113202 Hom.: 8 Cov.: 23

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.0189

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00563

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000710

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.00982

GnomAD2 exomes AF: 0.0101 AC: 1845 AN: 183016 AF XY: 0.00984

Gnomad AFR exome AF: 0.00244

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.00803

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00632

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.00907

GnomAD4 exome AF: 0.0155 AC: 16220 AN: 1044270 Hom.: 113 Cov.: 24 AF XY: 0.0144 AC XY: 4606 AN XY: 320118

African (AFR) AF: 0.00220 AC: 56 AN: 25431

American (AMR) AF: 0.00438 AC: 154 AN: 35153

Ashkenazi Jewish (ASJ) AF: 0.00756 AC: 144 AN: 19046

East Asian (EAS) AF: 0.00 AC: 0 AN: 29992

South Asian (SAS) AF: 0.00230 AC: 122 AN: 52984

European-Finnish (FIN) AF: 0.00746 AC: 302 AN: 40488

Middle Eastern (MID) AF: 0.00125 AC: 5 AN: 4016

European-Non Finnish (NFE) AF: 0.0187 AC: 14831 AN: 792777

Other (OTH) AF: 0.0137 AC: 606 AN: 44383

GnomAD4 genome AF: 0.0113 AC: 1284 AN: 113254 Hom.: 8 Cov.: 23 AF XY: 0.00994 AC XY: 352 AN XY: 35412

African (AFR) AF: 0.00265 AC: 83 AN: 31275

American (AMR) AF: 0.00549 AC: 59 AN: 10742

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 15 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3615

South Asian (SAS) AF: 0.000712 AC: 2 AN: 2810

European-Finnish (FIN) AF: 0.00651 AC: 41 AN: 6295

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.0198 AC: 1055 AN: 53403

Other (OTH) AF: 0.00971 AC: 15 AN: 1545

Alfa AF: 0.0165 Hom.: 130

Bravo AF: 0.0104

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Glycogen storage disease IXa1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		4.6
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.060
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: rs140662042; hg19: chrX-18959796;