rs149991825

chrX-18920043-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000292.3(PHKA2):c.1952C>A(p.Thr651Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,200,405 control chromosomes in the GnomAD database, including 22 homozygotes. There are 1,290 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., 119 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (22 hom. 1171 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00300

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 (MetaRNN=0.00387156).
• BP6: Variant X-18920043-G-T is Benign according to our data. Variant chrX-18920043-G-T is described in ClinVar as [Benign]. Clinvar id is 255770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00346 (388/112099) while in subpopulation AMR AF= 0.0186 (196/10563). AF 95% confidence interval is 0.0164. There are 0 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 118 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.1952C>A	p.Thr651Asn	missense_variant	18/33	ENST00000379942.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.1952C>A	p.Thr651Asn	missense_variant	18/33	1	NM_000292.3	P1

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 389 AN: 112049 Hom.: 0 Cov.: 23 AF XY: 0.00345 AC XY: 118 AN XY: 34215

Gnomad AFR AF: 0.000876

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00196

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00242

Gnomad OTH AF: 0.00601

GnomAD3 exomes AF: 0.00573 AC: 1043 AN: 182026 Hom.: 12 AF XY: 0.00478 AC XY: 319 AN XY: 66768

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.000935

Gnomad EAS exome AF: 0.00137

Gnomad SAS exome AF: 0.000996

Gnomad FIN exome AF: 0.00244

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00487

GnomAD4 exome AF: 0.00335 AC: 3649 AN: 1088306 Hom.: 22 Cov.: 27 AF XY: 0.00330 AC XY: 1171 AN XY: 354456

Gnomad4 AFR exome AF: 0.000305

Gnomad4 AMR exome AF: 0.0270

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.000779

Gnomad4 FIN exome AF: 0.00242

Gnomad4 NFE exome AF: 0.00274

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.00346 AC: 388 AN: 112099 Hom.: 0 Cov.: 23 AF XY: 0.00347 AC XY: 119 AN XY: 34275

Gnomad4 AFR AF: 0.000874

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.00264

Gnomad4 EAS AF: 0.00197

Gnomad4 SAS AF: 0.000744

Gnomad4 FIN AF: 0.00181

Gnomad4 NFE AF: 0.00242

Gnomad4 OTH AF: 0.00594

Alfa AF: 0.00297 Hom.: 122

Bravo AF: 0.00537

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00277 AC: 8

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00253 AC: 17

ExAC AF: 0.00471 AC: 572

EpiCase AF: 0.00338

EpiControl AF: 0.00225

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	Mar 11, 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	-	- -

Glycogen storage disease IXa1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.52
Dann	Benign	0.66
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.031
MVP		0.25
MPC		0.25
ClinPred		0.0031	T
GERP RS		-1.3
Varity_R		0.072
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149991825; hg19: chrX-18938161;