rs143732206

Variant names:

• chrX-18918741-T-C
• rs143732206
• NM_000292.3:c.2077A>G

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.2077A>G​(p.Ile693Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00973 in 1,208,559 control chromosomes in the GnomAD database, including 45 homozygotes. There are 3,989 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (1 hom., 200 hem., cov: 23)
  • Exomes 𝑓: 0.010 (44 hom. 3789 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.319
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00425151).
• BP6: Variant X-18918741-T-C is Benign according to our data. Variant chrX-18918741-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00676 (759/112314) while in subpopulation SAS AF = 0.016 (43/2691). AF 95% confidence interval is 0.0122. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 200 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.2077A>G	p.Ile693Val	missense	Exon 19 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.2077A>G	p.Ile693Val	missense	Exon 19 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.2077A>G	p.Ile693Val	missense	Exon 19 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.2077A>G	p.Ile693Val	missense	Exon 19 of 33	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.2077A>G	p.Ile693Val	missense	Exon 19 of 33	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.2077A>G	p.Ile693Val	missense	Exon 19 of 33	ENSP00000624789.1

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 759 AN: 112260 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0161

Gnomad AMR AF: 0.00274

Gnomad ASJ AF: 0.00491

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00995

GnomAD2 exomes AF: 0.00769 AC: 1411 AN: 183395 AF XY: 0.00911

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00277

Gnomad ASJ exome AF: 0.00574

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00662

GnomAD4 exome AF: 0.0100 AC: 10995 AN: 1096245 Hom.: 44 Cov.: 30 AF XY: 0.0105 AC XY: 3789 AN XY: 361675

African (AFR) AF: 0.00163 AC: 43 AN: 26368

American (AMR) AF: 0.00267 AC: 94 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 112 AN: 19377

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30198

South Asian (SAS) AF: 0.0165 AC: 891 AN: 54105

European-Finnish (FIN) AF: 0.00178 AC: 72 AN: 40531

Middle Eastern (MID) AF: 0.0271 AC: 112 AN: 4128

European-Non Finnish (NFE) AF: 0.0110 AC: 9285 AN: 840289

Other (OTH) AF: 0.00836 AC: 385 AN: 46042

GnomAD4 genome AF: 0.00676 AC: 759 AN: 112314 Hom.: 1 Cov.: 23 AF XY: 0.00580 AC XY: 200 AN XY: 34480

African (AFR) AF: 0.00132 AC: 41 AN: 30948

American (AMR) AF: 0.00274 AC: 29 AN: 10597

Ashkenazi Jewish (ASJ) AF: 0.00491 AC: 13 AN: 2647

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3575

South Asian (SAS) AF: 0.0160 AC: 43 AN: 2691

European-Finnish (FIN) AF: 0.00113 AC: 7 AN: 6171

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.0112 AC: 596 AN: 53257

Other (OTH) AF: 0.00982 AC: 15 AN: 1527

Alfa AF: 0.0100 Hom.: 503

Bravo AF: 0.00628

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0104 AC: 30

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.0111 AC: 75

ExAC AF: 0.00874 AC: 1061

EpiCase AF: 0.0107

EpiControl AF: 0.0120

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0040
DANN	Benign	0.35
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.32
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.27
Sift	Benign	0.80	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MVP		0.29
MPC		0.18
ClinPred		0.0015	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.26
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143732206; hg19: chrX-18936859; COSMIC: COSV108223416;