X-72580371-CAG-C

Variant names:

• chrX-72580371-CAG-C
• rs3070316
• NM_002637.4:c.*629_*630delCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002637.4(PHKA1):​c.*629_*630delCT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0842 in 112,512 control chromosomes in the GnomAD database, including 395 homozygotes. There are 2,810 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.084 (392 hom., 2802 hem., cov: 20)
  • Exomes 𝑓: 0.067 (3 hom. 8 hem.)
• Consequence: PHKA1 NM_002637.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.754
• Publications: 0 publications found

Genes affected

PHKA1 (HGNC:8925): (phosphorylase kinase regulatory subunit alpha 1) 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 skeletal muscle 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 9D, also known as X-linked muscle glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. A pseudogene has been found on chromosome 1.[provided by RefSeq, Feb 2010]

PHKA1 Gene-Disease associations (from GenCC):

• glycogen storage disease IXd

  Inheritance: XL, AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant X-72580371-CAG-C is Benign according to our data. Variant chrX-72580371-CAG-C is described in ClinVar as [Benign]. Clinvar id is 368638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.*629_*630delCT		3_prime_UTR_variant	Exon 32 of 32	ENST00000373542.9	NP_002628.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9	c.*629_*630delCT		3_prime_UTR_variant	Exon 32 of 32	1	NM_002637.4	ENSP00000362643.4
PHKA1	ENST00000339490.7	c.*629_*630delCT		3_prime_UTR_variant	Exon 31 of 31	1		ENSP00000342469.3
PHKA1	ENST00000541944.5	c.*629_*630delCT		3_prime_UTR_variant	Exon 30 of 30	1		ENSP00000441251.1
PHKA1	ENST00000373545.7	c.*629_*630delCT		3_prime_UTR_variant	Exon 32 of 32	5		ENSP00000362646.3

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 9437 AN: 111836 Hom.: 393 Cov.: 20

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0294

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.0945

Gnomad MID AF: 0.0625

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0719

GnomAD4 exome AF: 0.0674 AC: 42 AN: 623 Hom.: 3 AF XY: 0.0650 AC XY: 8 AN XY: 123

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00980 AC: 1 AN: 102

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.400 AC: 2 AN: 5

South Asian (SAS) AF: 0.0500 AC: 1 AN: 20

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1

European-Non Finnish (NFE) AF: 0.0802 AC: 38 AN: 474

Other (OTH) AF: 0.00 AC: 0 AN: 17

GnomAD4 genome AF: 0.0843 AC: 9430 AN: 111889 Hom.: 392 Cov.: 20 AF XY: 0.0822 AC XY: 2802 AN XY: 34105

African (AFR) AF: 0.0194 AC: 598 AN: 30895

American (AMR) AF: 0.0386 AC: 410 AN: 10610

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 297 AN: 2642

East Asian (EAS) AF: 0.262 AC: 927 AN: 3533

South Asian (SAS) AF: 0.187 AC: 498 AN: 2666

European-Finnish (FIN) AF: 0.0945 AC: 566 AN: 5988

Middle Eastern (MID) AF: 0.0639 AC: 14 AN: 219

European-Non Finnish (NFE) AF: 0.113 AC: 5990 AN: 53120

Other (OTH) AF: 0.0716 AC: 110 AN: 1536

Alfa AF: 0.0924 Hom.: 521

Bravo AF: 0.0772

Asia WGS AF: 0.214 AC: 537 AN: 2522

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen phosphorylase kinase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75
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: rs3070316; hg19: chrX-71800221;