rs10521685

Variant names:

• chrX-18925991-A-G
• rs10521685
• NM_000292.3:c.1460-214T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000292.3(PHKA2):​c.1460-214T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 111,803 control chromosomes in the GnomAD database, including 78 homozygotes. There are 928 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.032 (78 hom., 928 hem., cov: 23)
• Consequence: PHKA2 NM_000292.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.412
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-18925991-A-G is Benign according to our data. Variant chrX-18925991-A-G is described in ClinVar as Benign. ClinVar VariationId is 1263469.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3	c.1460-214T>C		intron_variant	Intron 14 of 32	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5	c.1460-214T>C		intron_variant	Intron 14 of 32	1	NM_000292.3	ENSP00000369274.4
PHKA2	ENST00000464455.1	n.29-214T>C		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 3529 AN: 111750 Hom.: 78 Cov.: 23

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.0146

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00117

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0345

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0317 AC: 3542 AN: 111803 Hom.: 78 Cov.: 23 AF XY: 0.0273 AC XY: 928 AN XY: 33979

African (AFR) AF: 0.0865 AC: 2665 AN: 30799

American (AMR) AF: 0.0126 AC: 132 AN: 10507

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 13 AN: 2647

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3564

South Asian (SAS) AF: 0.0150 AC: 40 AN: 2672

European-Finnish (FIN) AF: 0.00117 AC: 7 AN: 5968

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.0116 AC: 619 AN: 53218

Other (OTH) AF: 0.0341 AC: 52 AN: 1527

Alfa AF: 0.0204 Hom.: 166

Bravo AF: 0.0341

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 22, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.21
DANN	Benign	0.22
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10521685; hg19: chrX-18944109;