rs61729452

Positions:

• chrX-18907083-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000292.3(PHKA2):​c.2532G>A​(p.Leu844=) 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 (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 255774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18907083-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKA2	NM_000292.3	c.2532G>A	p.Leu844=	synonymous_variant	23/33	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5	c.2532G>A	p.Leu844=	synonymous_variant	23/33	1	NM_000292.3	ENSP00000369274	P1

Frequencies

GnomAD3 genomes AF: 0.00924 AC: 1037 AN: 112186 Hom.: 7 Cov.: 23 AF XY: 0.00786 AC XY: 270 AN XY: 34332

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

GnomAD3 exomes AF: 0.00939 AC: 1297 AN: 138133 Hom.: 5 AF XY: 0.00951 AC XY: 410 AN XY: 43101

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 SAS exome AF: 0.00470

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

Gnomad4 AFR exome AF: 0.00217

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.00408

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00455

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0111

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

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.00507

Gnomad4 ASJ AF: 0.00452

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.00729

Gnomad4 NFE AF: 0.0157

Gnomad4 OTH AF: 0.00786

Alfa AF: 0.0117 Hom.: 97

Bravo AF: 0.00887

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Glycogen storage disease IXa1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.0
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs61729452; hg19: chrX-18925201;