rs16980929

Variant names:

• chrX-18929306-C-T
• rs16980929
• NM_000292.3:c.1246G>A

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 7.67
• Publications: 4 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), Genomics England PanelApp, Ambry Genetics
• glycogen storage disease due to liver phosphorylase kinase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious 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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 151 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000292.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	NM_000292.3	MANE Select	c.1246G>A	p.Gly416Arg	missense splice_region	Exon 13 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.1246G>A	p.Gly416Arg	missense splice_region	Exon 13 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.1246G>A	p.Gly416Arg	missense splice_region	Exon 13 of 32	NP_001427729.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	ENST00000379942.5	TSL:1 MANE Select	c.1246G>A	p.Gly416Arg	missense splice_region	Exon 13 of 33	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.1246G>A	p.Gly416Arg	missense splice_region	Exon 13 of 33	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.1246G>A	p.Gly416Arg	missense splice_region	Exon 13 of 33	ENSP00000624789.1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 537 AN: 112098 Hom.: 1 Cov.: 24

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

GnomAD2 exomes AF: 0.00147 AC: 189 AN: 128158 AF XY: 0.00106

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 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

African (AFR) AF: 0.0156 AC: 383 AN: 24484

American (AMR) AF: 0.00149 AC: 45 AN: 30290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18625

East Asian (EAS) AF: 0.00 AC: 0 AN: 27831

South Asian (SAS) AF: 0.000141 AC: 7 AN: 49554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38117

Middle Eastern (MID) AF: 0.000999 AC: 4 AN: 4005

European-Non Finnish (NFE) AF: 0.0000152 AC: 12 AN: 788779

Other (OTH) AF: 0.00115 AC: 50 AN: 43482

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

African (AFR) AF: 0.0166 AC: 514 AN: 30899

American (AMR) AF: 0.00160 AC: 17 AN: 10602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2707

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53194

Other (OTH) AF: 0.00326 AC: 5 AN: 1533

Alfa AF: 0.00178 Hom.: 110

Bravo AF: 0.00557

ESP6500AA AF: 0.0183 AC: 70

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00142 AC: 152

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	Glycogen storage disease IXa1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.7
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
Mutation Taster		=9/91	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16980929; hg19: chrX-18947424;