rs17313469

chrX-18954379-C-G

Variant summary

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

The NM_000292.3(PHKA2):c.112G>C(p.Glu38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,210,349 control chromosomes in the GnomAD database, including 337 homozygotes. There are 10,659 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (24 hom., 656 hem., cov: 23)
  • Exomes 𝑓: 0.028 (313 hom. 10003 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.40

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008445859).
• BP6: Variant X-18954379-C-G is Benign according to our data. Variant chrX-18954379-C-G is described in ClinVar as [Benign]. Clinvar id is 255768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18954379-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0203 (2291/112838) while in subpopulation NFE AF= 0.0293 (1565/53328). AF 95% confidence interval is 0.0281. There are 24 homozygotes in gnomad4. There are 656 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.112G>C	p.Glu38Gln	missense_variant	2/33	ENST00000379942.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.112G>C	p.Glu38Gln	missense_variant	2/33	1	NM_000292.3	P1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 2294 AN: 112782 Hom.: 24 Cov.: 23 AF XY: 0.0188 AC XY: 656 AN XY: 34928

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.0948

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.000561

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0553

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0304

GnomAD3 exomes AF: 0.0198 AC: 3617 AN: 182784 Hom.: 30 AF XY: 0.0209 AC XY: 1406 AN XY: 67258

Gnomad AFR exome AF: 0.00403

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.0326

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00398

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0283 AC: 31076 AN: 1097511 Hom.: 313 Cov.: 30 AF XY: 0.0276 AC XY: 10003 AN XY: 362935

Gnomad4 AFR exome AF: 0.00405

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.0329

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00460

Gnomad4 FIN exome AF: 0.0190

Gnomad4 NFE exome AF: 0.0326

Gnomad4 OTH exome AF: 0.0272

GnomAD4 genome AF: 0.0203 AC: 2291 AN: 112838 Hom.: 24 Cov.: 23 AF XY: 0.0187 AC XY: 656 AN XY: 34994

Gnomad4 AFR AF: 0.00388

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0332

Gnomad4 EAS AF: 0.000563

Gnomad4 SAS AF: 0.00582

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.0293

Gnomad4 OTH AF: 0.0300

Alfa AF: 0.0283 Hom.: 609

Bravo AF: 0.0218

TwinsUK AF: 0.0324 AC: 120

ALSPAC AF: 0.0312 AC: 90

ESP6500AA AF: 0.00391 AC: 15

ESP6500EA AF: 0.0360 AC: 242

ExAC AF: 0.0202 AC: 2446

EpiCase AF: 0.0346

EpiControl AF: 0.0366

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2017	- -

Glycogen storage disease IXa1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.059	P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Benign	0.32	T
Polyphen		0.0030	B
Vest4		0.030
MPC		0.93
ClinPred		0.0084	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.60

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: rs17313469; hg19: chrX-18972497; COSMIC: COSV66054173;