rs16980929

chrX-18929306-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_000292.3(PHKA2):c.1246G>A(p.Gly416Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,137,319 control chromosomes in the GnomAD database, including 5 homozygotes. There are 288 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., 151 hem., cov: 24)
  • Exomes 𝑓: 0.00049 (4 hom. 137 hem.)
• Consequence: PHKA2 NM_000292.3 missense, splice_region
• Scores: Splicing: ADA: 0.9761
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 7.67

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant X-18929306-C-T is Benign according to our data. Variant chrX-18929306-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 506571.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 = 0.0048 (538/112152) while in subpopulation AFR AF= 0.0166 (514/30899). AF 95% confidence interval is 0.0154. There are 1 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 151 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.1246G>A	p.Gly416Arg	missense_variant, splice_region_variant	13/33	ENST00000379942.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.1246G>A	p.Gly416Arg	missense_variant, splice_region_variant	13/33	1	NM_000292.3	P1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 537 AN: 112098 Hom.: 1 Cov.: 24 AF XY: 0.00440 AC XY: 151 AN XY: 34324

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.0000376

Gnomad OTH AF: 0.00330

GnomAD3 exomes AF: 0.00147 AC: 189 AN: 128158 Hom.: 2 AF XY: 0.00106 AC XY: 45 AN XY: 42474

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000592

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.000489 AC: 501 AN: 1025167 Hom.: 4 Cov.: 24 AF XY: 0.000436 AC XY: 137 AN XY: 313907

Gnomad4 AFR exome AF: 0.0156

Gnomad4 AMR exome AF: 0.00149

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000152

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.00480 AC: 538 AN: 112152 Hom.: 1 Cov.: 24 AF XY: 0.00439 AC XY: 151 AN XY: 34388

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.00160

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00326

Alfa AF: 0.000626 Hom.: 33

Bravo AF: 0.00557

ESP6500AA AF: 0.0183 AC: 70

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00142 AC: 152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 17, 2017

- -

Glycogen storage disease IXa1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.71
MutPred		0.31		Gain of relative solvent accessibility (P = 0.1259);
MVP		0.75
MPC		0.91
ClinPred		0.031	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16980929; hg19: chrX-18947424;