X-18907981-C-T

Variant names:

• chrX-18907981-C-T
• rs61733281
• NM_000292.3:c.2436G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000292.3(PHKA2):​c.2436G>A​(p.Gly812Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,209,092 control chromosomes in the GnomAD database, including 64 homozygotes. There are 3,825 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G812G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (3 hom., 249 hem., cov: 23)
  • Exomes 𝑓: 0.010 (61 hom. 3576 hem.)
• Consequence: PHKA2 NM_000292.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.11
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-18907981-C-T is Benign according to our data. Variant chrX-18907981-C-T is described in ClinVar as Benign. ClinVar VariationId is 255773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00731 (818/111916) while in subpopulation NFE AF = 0.0112 (595/53127). AF 95% confidence interval is 0.0105. There are 3 homozygotes in GnomAd4. There are 249 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2436G>A	p.Gly812Gly	synonymous	Exon 22 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.2436G>A	p.Gly812Gly	synonymous	Exon 22 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.2436G>A	p.Gly812Gly	synonymous	Exon 22 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.2436G>A	p.Gly812Gly	synonymous	Exon 22 of 33	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.2436G>A	p.Gly812Gly	synonymous	Exon 22 of 33	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.2421G>A	p.Gly807Gly	synonymous	Exon 22 of 33	ENSP00000624789.1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 819 AN: 111860 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.00153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00673

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.0598

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00775 AC: 1423 AN: 183527 AF XY: 0.00796

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.00769

Gnomad ASJ exome AF: 0.000534

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0102 AC: 11155 AN: 1097176 Hom.: 61 Cov.: 30 AF XY: 0.00986 AC XY: 3576 AN XY: 362536

African (AFR) AF: 0.00220 AC: 58 AN: 26375

American (AMR) AF: 0.00761 AC: 268 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 26 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00292 AC: 158 AN: 54117

European-Finnish (FIN) AF: 0.00950 AC: 385 AN: 40533

Middle Eastern (MID) AF: 0.0305 AC: 126 AN: 4128

European-Non Finnish (NFE) AF: 0.0116 AC: 9735 AN: 841175

Other (OTH) AF: 0.00866 AC: 399 AN: 46057

GnomAD4 genome AF: 0.00731 AC: 818 AN: 111916 Hom.: 3 Cov.: 23 AF XY: 0.00730 AC XY: 249 AN XY: 34088

African (AFR) AF: 0.00152 AC: 47 AN: 30822

American (AMR) AF: 0.00673 AC: 71 AN: 10555

Ashkenazi Jewish (ASJ) AF: 0.000756 AC: 2 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3543

South Asian (SAS) AF: 0.00112 AC: 3 AN: 2672

European-Finnish (FIN) AF: 0.0113 AC: 69 AN: 6124

Middle Eastern (MID) AF: 0.0607 AC: 13 AN: 214

European-Non Finnish (NFE) AF: 0.0112 AC: 595 AN: 53127

Other (OTH) AF: 0.0117 AC: 18 AN: 1536

Alfa AF: 0.00829 Hom.: 96

Bravo AF: 0.00681

EpiCase AF: 0.0119

EpiControl AF: 0.0106

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.3
DANN	Benign	0.48
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs61733281; hg19: chrX-18926099; COSMIC: COSV101176883; COSMIC: COSV101176883;