rs148877451

chrX-18908068-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000292.3(PHKA2):c.2361-12A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,203,196 control chromosomes in the GnomAD database, including 221 homozygotes. There are 1,689 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (112 hom., 785 hem., cov: 23)
  • Exomes 𝑓: 0.0031 (109 hom. 904 hem.)
• Consequence: PHKA2 NM_000292.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002485
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.99

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant X-18908068-T-G is Benign according to our data. Variant chrX-18908068-T-G is described in ClinVar as [Benign]. Clinvar id is 255772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.2361-12A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000379942.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.2361-12A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000292.3	P1

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 3057 AN: 111371 Hom.: 112 Cov.: 23 AF XY: 0.0232 AC XY: 782 AN XY: 33635

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.000491

Gnomad OTH AF: 0.0200

GnomAD3 exomes AF: 0.00844 AC: 1546 AN: 183079 Hom.: 47 AF XY: 0.00569 AC XY: 385 AN XY: 67609

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000315

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.00530

GnomAD4 exome AF: 0.00309 AC: 3376 AN: 1091773 Hom.: 109 Cov.: 30 AF XY: 0.00253 AC XY: 904 AN XY: 357229

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00565

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000315

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.00649

GnomAD4 genome AF: 0.0275 AC: 3060 AN: 111423 Hom.: 112 Cov.: 23 AF XY: 0.0233 AC XY: 785 AN XY: 33697

Gnomad4 AFR AF: 0.0951

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.000380

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.000491

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0117 Hom.: 60

Bravo AF: 0.0313

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Mar 14, 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. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 17, 2023	- -

Glycogen storage disease IXa1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.35
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.060
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: rs148877451; hg19: chrX-18926186;