rs139803629

Positions:

• chrX-72611092-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002637.4(PHKA1):​c.2462G>A​(p.Arg821His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,203,695 control chromosomes in the GnomAD database, including 12 homozygotes. There are 1,647 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R821C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., 70 hem., cov: 22)
  • Exomes 𝑓: 0.0046 (10 hom. 1577 hem.)
• Consequence: PHKA1 NM_002637.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.96

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009200335).
• BP6: Variant X-72611092-C-T is Benign according to our data. Variant chrX-72611092-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-72611092-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00274 (305/111410) while in subpopulation NFE AF= 0.00496 (263/53061). AF 95% confidence interval is 0.00446. There are 2 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA1	NM_002637.4	c.2462G>A	p.Arg821His	missense_variant	22/32	ENST00000373542.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA1	ENST00000373542.9	c.2462G>A	p.Arg821His	missense_variant	22/32	1	NM_002637.4	P4

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 305 AN: 111357 Hom.: 2 Cov.: 22 AF XY: 0.00209 AC XY: 70 AN XY: 33537

Gnomad AFR AF: 0.000783

Gnomad AMI AF: 0.00876

Gnomad AMR AF: 0.000768

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00496

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.00331 AC: 605 AN: 182660 Hom.: 2 AF XY: 0.00316 AC XY: 213 AN XY: 67366

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000316

Gnomad FIN exome AF: 0.000814

Gnomad NFE exome AF: 0.00638

Gnomad OTH exome AF: 0.00445

GnomAD4 exome AF: 0.00462 AC: 5043 AN: 1092285 Hom.: 10 Cov.: 28 AF XY: 0.00440 AC XY: 1577 AN XY: 358009

Gnomad4 AFR exome AF: 0.000609

Gnomad4 AMR exome AF: 0.00137

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000259

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00564

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.00274 AC: 305 AN: 111410 Hom.: 2 Cov.: 22 AF XY: 0.00208 AC XY: 70 AN XY: 33600

Gnomad4 AFR AF: 0.000781

Gnomad4 AMR AF: 0.000767

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000167

Gnomad4 NFE AF: 0.00496

Gnomad4 OTH AF: 0.00199

Alfa AF: 0.00440 Hom.: 181

Bravo AF: 0.00277

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00431 AC: 29

ExAC AF: 0.00400 AC: 486

EpiCase AF: 0.00458

EpiControl AF: 0.00547

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Glycogen storage disease IXd Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;D;.;.;D
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D;T;T;T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.0092	T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.7	L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.10	T;D;T;D;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.034	B;.;B;.;.
Vest4		0.12
MVP		0.77
MPC		0.38
ClinPred		0.022	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs139803629; hg19: chrX-71830942; COSMIC: COSV99045068;