rs149219369

Variant names:

• chrX-18941651-T-G
• rs149219369
• NM_000292.3:c.742A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000292.3(PHKA2):​c.742A>C​(p.Arg248Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,172,943 control chromosomes in the GnomAD database, including 3 homozygotes. There are 602 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 42 hem., cov: 23)
  • Exomes 𝑓: 0.0018 (3 hom. 560 hem.)
• Consequence: PHKA2 NM_000292.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.63
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-18941651-T-G is Benign according to our data. Variant chrX-18941651-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0013 (147/113213) while in subpopulation NFE AF = 0.0023 (123/53430). AF 95% confidence interval is 0.00197. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 42 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.742A>C	p.Arg248Arg	synonymous	Exon 8 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.742A>C	p.Arg248Arg	synonymous	Exon 8 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.742A>C	p.Arg248Arg	synonymous	Exon 8 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.742A>C	p.Arg248Arg	synonymous	Exon 8 of 33	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.742A>C	p.Arg248Arg	synonymous	Exon 8 of 33	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.742A>C	p.Arg248Arg	synonymous	Exon 8 of 33	ENSP00000624789.1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 147 AN: 113213 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000747

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: 0.00230

Gnomad OTH AF: 0.00197

GnomAD2 exomes AF: 0.00119 AC: 219 AN: 183338 AF XY: 0.00114

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.00184 AC: 1949 AN: 1059730 Hom.: 3 Cov.: 25 AF XY: 0.00170 AC XY: 560 AN XY: 330144

African (AFR) AF: 0.000117 AC: 3 AN: 25708

American (AMR) AF: 0.000654 AC: 23 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19147

East Asian (EAS) AF: 0.00 AC: 0 AN: 30055

South Asian (SAS) AF: 0.0000375 AC: 2 AN: 53293

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40516

Middle Eastern (MID) AF: 0.000494 AC: 2 AN: 4050

European-Non Finnish (NFE) AF: 0.00229 AC: 1844 AN: 806909

Other (OTH) AF: 0.00163 AC: 73 AN: 44873

GnomAD4 genome AF: 0.00130 AC: 147 AN: 113213 Hom.: 0 Cov.: 23 AF XY: 0.00119 AC XY: 42 AN XY: 35341

African (AFR) AF: 0.000416 AC: 13 AN: 31227

American (AMR) AF: 0.000747 AC: 8 AN: 10715

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3630

South Asian (SAS) AF: 0.00 AC: 0 AN: 2807

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6293

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00230 AC: 123 AN: 53430

Other (OTH) AF: 0.00197 AC: 3 AN: 1521

Alfa AF: 0.00189 Hom.: 13

Bravo AF: 0.00137

EpiCase AF: 0.00229

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.1
DANN	Benign	0.72
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs149219369; hg19: chrX-18959769; COSMIC: COSV66054365;