rs149991825

Variant names:

• chrX-18920043-G-T
• rs149991825
• NM_000292.3:c.1952C>A

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.1952C>A​(p.Thr651Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,200,405 control chromosomes in the GnomAD database, including 22 homozygotes. There are 1,290 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T651T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., 119 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (22 hom. 1171 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.00300
• Publications: 1 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=0.00387156).
• BP6: Variant X-18920043-G-T is Benign according to our data. Variant chrX-18920043-G-T is described in ClinVar as Benign. ClinVar VariationId is 255770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00346 (388/112099) while in subpopulation AMR AF = 0.0186 (196/10563). AF 95% confidence interval is 0.0164. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 119 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.1952C>A	p.Thr651Asn	missense	Exon 18 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.1952C>A	p.Thr651Asn	missense	Exon 18 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.1952C>A	p.Thr651Asn	missense	Exon 18 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.1952C>A	p.Thr651Asn	missense	Exon 18 of 33	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.1952C>A	p.Thr651Asn	missense	Exon 18 of 33	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.1952C>A	p.Thr651Asn	missense	Exon 18 of 33	ENSP00000624789.1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 389 AN: 112049 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000876

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00196

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00242

Gnomad OTH AF: 0.00601

GnomAD2 exomes AF: 0.00573 AC: 1043 AN: 182026 AF XY: 0.00478

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.000935

Gnomad EAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00244

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00487

GnomAD4 exome AF: 0.00335 AC: 3649 AN: 1088306 Hom.: 22 Cov.: 27 AF XY: 0.00330 AC XY: 1171 AN XY: 354456

African (AFR) AF: 0.000305 AC: 8 AN: 26252

American (AMR) AF: 0.0270 AC: 950 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 20 AN: 19327

East Asian (EAS) AF: 0.00292 AC: 88 AN: 30186

South Asian (SAS) AF: 0.000779 AC: 42 AN: 53936

European-Finnish (FIN) AF: 0.00242 AC: 96 AN: 39726

Middle Eastern (MID) AF: 0.000972 AC: 4 AN: 4117

European-Non Finnish (NFE) AF: 0.00274 AC: 2287 AN: 833782

Other (OTH) AF: 0.00336 AC: 154 AN: 45786

GnomAD4 genome AF: 0.00346 AC: 388 AN: 112099 Hom.: 0 Cov.: 23 AF XY: 0.00347 AC XY: 119 AN XY: 34275

African (AFR) AF: 0.000874 AC: 27 AN: 30905

American (AMR) AF: 0.0186 AC: 196 AN: 10563

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 7 AN: 2651

East Asian (EAS) AF: 0.00197 AC: 7 AN: 3557

South Asian (SAS) AF: 0.000744 AC: 2 AN: 2689

European-Finnish (FIN) AF: 0.00181 AC: 11 AN: 6082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00242 AC: 129 AN: 53237

Other (OTH) AF: 0.00594 AC: 9 AN: 1516

Alfa AF: 0.00285 Hom.: 125

Bravo AF: 0.00537

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00277 AC: 8

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.00471 AC: 572

EpiCase AF: 0.00338

EpiControl AF: 0.00225

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.52
DANN	Benign	0.66
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.0030
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.031
MVP		0.25
MPC		0.25
ClinPred		0.0031	T
GERP RS		-1.3
Varity_R		0.072
gMVP		0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149991825; hg19: chrX-18938161;