X-72581005-T-C

Variant names:

• chrX-72581005-T-C
• rs782257959
• NM_002637.4:c.3669A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002637.4(PHKA1):​c.3669A>G​(p.Gln1223Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,096,822 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: PHKA1 NM_002637.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.628
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-72581005-T-C is Benign according to our data. Variant chrX-72581005-T-C is described in ClinVar as [Benign]. Clinvar id is 368642.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.628 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.3669A>G	p.Gln1223Gln	synonymous_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.3669A>G	p.Gln1223Gln	synonymous_variant	Exon 32 of 32	1	NM_002637.4	ENSP00000362643.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000332 AC: 6 AN: 180639 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 9 AN: 1096822 Hom.: 0 Cov.: 29 AF XY: 0.00000828 AC XY: 3 AN XY: 362230

African (AFR) AF: 0.0000758 AC: 2 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 53927

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841123

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

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease IXd Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.3
DANN	Benign	0.29
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

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: rs782257959; hg19: chrX-71800855;