rs61733284

chrX-18941544-A-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.849T>A(p.Ile283=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,208,421 control chromosomes in the GnomAD database, including 45 homozygotes. There are 995 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., 394 hem., cov: 23)
  • Exomes 𝑓: 0.0019 (21 hom. 601 hem.)
• Consequence: PHKA2 NM_000292.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.16

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=-0.48).
• BP6: Variant X-18941544-A-T is Benign according to our data. Variant chrX-18941544-A-T is described in ClinVar as [Benign]. Clinvar id is 255779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1464/112491) while in subpopulation AFR AF= 0.042 (1302/30964). AF 95% confidence interval is 0.0402. There are 24 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.849T>A	p.Ile283=	synonymous_variant	8/33	ENST00000379942.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.849T>A	p.Ile283=	synonymous_variant	8/33	1	NM_000292.3	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1462 AN: 112437 Hom.: 23 Cov.: 23 AF XY: 0.0114 AC XY: 394 AN XY: 34591

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00782

Gnomad ASJ AF: 0.00452

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000731

Gnomad OTH AF: 0.0165

GnomAD3 exomes AF: 0.00428 AC: 786 AN: 183449 Hom.: 12 AF XY: 0.00271 AC XY: 184 AN XY: 67887

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.00552

GnomAD4 exome AF: 0.00189 AC: 2073 AN: 1095930 Hom.: 21 Cov.: 29 AF XY: 0.00166 AC XY: 601 AN XY: 361332

Gnomad4 AFR exome AF: 0.0443

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00552

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000490

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.0130 AC: 1464 AN: 112491 Hom.: 24 Cov.: 23 AF XY: 0.0114 AC XY: 394 AN XY: 34655

Gnomad4 AFR AF: 0.0420

Gnomad4 AMR AF: 0.00781

Gnomad4 ASJ AF: 0.00452

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000731

Gnomad4 OTH AF: 0.0163

Alfa AF: 0.00865 Hom.: 46

Bravo AF: 0.0154

EpiCase AF: 0.00104

EpiControl AF: 0.000771

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	GeneDx	Jun 09, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 05, 2016	- -

Glycogen storage disease IXa1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	7.2
Dann	Benign	0.81
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: rs61733284; hg19: chrX-18959662;