rs773766679

Variant names:

• chrX-18899220-A-T
• rs773766679
• NM_000292.3:c.3064T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000292.3(PHKA2):​c.3064T>A​(p.Ser1022Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000854 in 1,206,307 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000092 (0 hom. 58 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.46
• 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), 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031959742).
• BP6: Variant X-18899220-A-T is Benign according to our data. Variant chrX-18899220-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522762.
• BS2: High Hemizygotes in GnomAdExome4 at 58 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.3064T>A	p.Ser1022Thr	missense	Exon 29 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.3064T>A	p.Ser1022Thr	missense	Exon 29 of 33	NP_001427734.1
	PHKA2	NM_001440802.1		c.2965T>A	p.Ser989Thr	missense	Exon 28 of 32	NP_001427731.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHKA2	ENST00000379942.5	TSL:1 MANE Select	c.3064T>A	p.Ser1022Thr	missense	Exon 29 of 33	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.3064T>A	p.Ser1022Thr	missense	Exon 29 of 33	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.3049T>A	p.Ser1017Thr	missense	Exon 29 of 33	ENSP00000624789.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112226 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 25 AN: 182670 AF XY: 0.000298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000923 AC: 101 AN: 1094081 Hom.: 0 Cov.: 29 AF XY: 0.000161 AC XY: 58 AN XY: 359555

African (AFR) AF: 0.00 AC: 0 AN: 26330

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19361

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30191

South Asian (SAS) AF: 0.00148 AC: 80 AN: 54037

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40313

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4129

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 838567

Other (OTH) AF: 0.000109 AC: 5 AN: 45953

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112226 Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1 AN XY: 34368

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30880

American (AMR) AF: 0.00 AC: 0 AN: 10639

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.000747 AC: 2 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53195

Other (OTH) AF: 0.00 AC: 0 AN: 1511

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disease IXa1 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.40		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.60
MPC		0.20
ClinPred		0.019	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.10
gMVP		0.45
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs773766679; hg19: chrX-18917338;