rs138395800

Variant names:

• chrX-18908052-G-A
• rs138395800
• NM_000292.3:c.2365C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000292.3(PHKA2):​c.2365C>T​(p.Pro789Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,208,972 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., 19 hem., cov: 23)
  • Exomes 𝑓: 0.000067 (0 hom. 16 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.62
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025713265).
• BP6: Variant X-18908052-G-A is Benign according to our data. Variant chrX-18908052-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000643 (72/112029) while in subpopulation AFR AF = 0.0022 (68/30852). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 19 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3	c.2365C>T	p.Pro789Ser	missense_variant	Exon 22 of 33	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5	c.2365C>T	p.Pro789Ser	missense_variant	Exon 22 of 33	1	NM_000292.3	ENSP00000369274.4

Frequencies

GnomAD3 genomes AF: 0.000643 AC: 72 AN: 111974 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.000240 AC: 44 AN: 183385 AF XY: 0.000118

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000675 AC: 74 AN: 1096943 Hom.: 0 Cov.: 30 AF XY: 0.0000442 AC XY: 16 AN XY: 362317

African (AFR) AF: 0.00246 AC: 65 AN: 26370

American (AMR) AF: 0.0000852 AC: 3 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840981

Other (OTH) AF: 0.000130 AC: 6 AN: 46053

GnomAD4 genome AF: 0.000643 AC: 72 AN: 112029 Hom.: 0 Cov.: 23 AF XY: 0.000555 AC XY: 19 AN XY: 34211

African (AFR) AF: 0.00220 AC: 68 AN: 30852

American (AMR) AF: 0.000282 AC: 3 AN: 10622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3530

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6153

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53138

Other (OTH) AF: 0.000652 AC: 1 AN: 1533

Alfa AF: 0.00104 Hom.: 10

Bravo AF: 0.000744

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease IXa1 Benign:1

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PHKA2-related disorder Benign:1

Mar 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

May 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.6
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.43
Sift	Benign	0.49	T
Sift4G	Benign	0.87	T
Polyphen		0.27	B
Vest4		0.46
MVP		0.74
MPC		0.51
ClinPred		0.053	T
GERP RS		4.9
Varity_R		0.42
gMVP		0.72
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs138395800; hg19: chrX-18926170;