rs61729452

Variant names:

• chrX-18907083-C-T
• rs61729452
• NM_000292.3:c.2532G>A

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.2532G>A​(p.Leu844Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,182,524 control chromosomes in the GnomAD database, including 96 homozygotes. There are 5,145 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. L844L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0092 (7 hom., 270 hem., cov: 23)
  • Exomes 𝑓: 0.014 (89 hom. 4875 hem.)
• Consequence: PHKA2 NM_000292.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.752
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.45).
• BP6: Variant X-18907083-C-T is Benign according to our data. Variant chrX-18907083-C-T is described in ClinVar as Benign. ClinVar VariationId is 255774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.752 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00924 (1037/112242) while in subpopulation NFE AF = 0.0157 (836/53160). AF 95% confidence interval is 0.0148. There are 7 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2532G>A	p.Leu844Leu	synonymous	Exon 23 of 33	NP_000283.1	P46019
	PHKA2	NM_001440805.1		c.2532G>A	p.Leu844Leu	synonymous	Exon 23 of 33	NP_001427734.1
	PHKA2	NM_001440800.1		c.2532G>A	p.Leu844Leu	synonymous	Exon 23 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.2532G>A	p.Leu844Leu	synonymous	Exon 23 of 33	ENSP00000369274.4	P46019
	PHKA2	ENST00000897868.1		c.2532G>A	p.Leu844Leu	synonymous	Exon 23 of 33	ENSP00000567927.1
	PHKA2	ENST00000954730.1		c.2517G>A	p.Leu839Leu	synonymous	Exon 23 of 33	ENSP00000624789.1

Frequencies

GnomAD3 genomes AF: 0.00924 AC: 1037 AN: 112186 Hom.: 7 Cov.: 23

Gnomad AFR AF: 0.00204

Gnomad AMI AF: 0.00586

Gnomad AMR AF: 0.00508

Gnomad ASJ AF: 0.00452

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00371

Gnomad FIN AF: 0.00729

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.00797

GnomAD2 exomes AF: 0.00939 AC: 1297 AN: 138133 AF XY: 0.00951

Gnomad AFR exome AF: 0.00201

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00452

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00972

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0143 AC: 15344 AN: 1070282 Hom.: 89 Cov.: 30 AF XY: 0.0141 AC XY: 4875 AN XY: 345606

African (AFR) AF: 0.00217 AC: 56 AN: 25841

American (AMR) AF: 0.00389 AC: 121 AN: 31093

Ashkenazi Jewish (ASJ) AF: 0.00408 AC: 77 AN: 18874

East Asian (EAS) AF: 0.00 AC: 0 AN: 28884

South Asian (SAS) AF: 0.00455 AC: 232 AN: 50972

European-Finnish (FIN) AF: 0.0117 AC: 457 AN: 38939

Middle Eastern (MID) AF: 0.00797 AC: 31 AN: 3888

European-Non Finnish (NFE) AF: 0.0168 AC: 13868 AN: 826747

Other (OTH) AF: 0.0111 AC: 502 AN: 45044

GnomAD4 genome AF: 0.00924 AC: 1037 AN: 112242 Hom.: 7 Cov.: 23 AF XY: 0.00785 AC XY: 270 AN XY: 34398

African (AFR) AF: 0.00204 AC: 63 AN: 30941

American (AMR) AF: 0.00507 AC: 54 AN: 10642

Ashkenazi Jewish (ASJ) AF: 0.00452 AC: 12 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00372 AC: 10 AN: 2687

European-Finnish (FIN) AF: 0.00729 AC: 45 AN: 6176

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.0157 AC: 836 AN: 53160

Other (OTH) AF: 0.00786 AC: 12 AN: 1526

Alfa AF: 0.0117 Hom.: 97

Bravo AF: 0.00887

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.0
DANN	Benign	0.59
PhyloP100		0.75
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)		0.0		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: rs61729452; hg19: chrX-18925201;