X-18907981-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000292.3(PHKA2):c.2436G>A(p.Gly812=) 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 (★★).

• 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:6
• Conservation: PhyloP100: -1.11

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 -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 id is 255773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18907981-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.2436G>A	p.Gly812=	synonymous_variant	22/33	ENST00000379942.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.2436G>A	p.Gly812=	synonymous_variant	22/33	1	NM_000292.3	P1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 819 AN: 111860 Hom.: 3 Cov.: 23 AF XY: 0.00732 AC XY: 249 AN XY: 34022

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

GnomAD3 exomes AF: 0.00775 AC: 1423 AN: 183527 Hom.: 7 AF XY: 0.00796 AC XY: 541 AN XY: 67955

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 SAS exome AF: 0.00367

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

Gnomad4 AFR exome AF: 0.00220

Gnomad4 AMR exome AF: 0.00761

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00292

Gnomad4 FIN exome AF: 0.00950

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00866

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

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.000756

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00112

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.0117

Alfa AF: 0.00622 Hom.: 34

Bravo AF: 0.00681

EpiCase AF: 0.0119

EpiControl AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Feb 22, 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:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	3.3
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs61733281; hg19: chrX-18926099; COSMIC: COSV101176883; COSMIC: COSV101176883;