rs149991825

Positions:

chrX-18920043-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.00300

Variant links:

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]

PHKA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 119 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKA2	NM_000292.3 linkuse as main transcript	c.1952C>A	p.Thr651Asn	missense_variant	18/33	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5 linkuse as main transcript	c.1952C>A	p.Thr651Asn	missense_variant	18/33	1	NM_000292.3	ENSP00000369274	P1

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

389

AN:

112049

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

118

AN XY:

34215

show subpopulations

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.:

AF XY:

0.00478

AC XY:

319

AN XY:

66768

show subpopulations

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.:

Cov.:

AF XY:

0.00330

AC XY:

1171

AN XY:

354456

show subpopulations

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.:

Cov.:

AF XY:

0.00347

AC XY:

119

AN XY:

34275

show subpopulations

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:

ALSPAC

AF:

0.00277

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.00471

AC:

572

EpiCase

AF:

0.00338

EpiControl

AF:

0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glycogen storage disease IXa1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.52

DANN

Benign

0.66

DEOGEN2

Benign

0.31

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.43

REVEL

Benign

0.14

Sift

Benign

0.42

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.031

MVP

0.25

MPC

0.25

ClinPred

0.0031

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over