rs143732206

Positions:

chrX-18918741-T-C

Variant summary

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

The NM_000292.3(PHKA2):c.2077A>G(p.Ile693Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00973 in 1,208,559 control chromosomes in the GnomAD database, including 45 homozygotes. There are 3,989 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 1 hom., 200 hem., cov: 23)

Exomes 𝑓: 0.010 ( 44 hom. 3789 hem. )

Consequence

PHKA2
NM_000292.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.319

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=0.00425151).

BP6

Variant X-18918741-T-C is Benign according to our data. Variant chrX-18918741-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 255771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18918741-T-C is described in Lovd as [Likely_benign]. Variant chrX-18918741-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00676 (759/112314) while in subpopulation SAS AF= 0.016 (43/2691). AF 95% confidence interval is 0.0122. There are 1 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 200 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKA2	NM_000292.3 linkuse as main transcript	c.2077A>G	p.Ile693Val	missense_variant	19/33	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.2077A>G	p.Ile693Val	missense_variant	19/33	1	NM_000292.3	ENSP00000369274	P1

Frequencies

GnomAD3 genomes

AF:

0.00676

AC:

759

AN:

112260

Hom.:

Cov.:

AF XY:

0.00581

AC XY:

200

AN XY:

34416

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.0161

Gnomad AMR

AF:

0.00274

Gnomad ASJ

AF:

0.00491

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0125

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00995

GnomAD3 exomes

AF:

0.00769

AC:

1411

AN:

183395

Hom.:

AF XY:

0.00911

AC XY:

618

AN XY:

67841

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00574

Gnomad EAS exome

AF:

0.0000721

Gnomad SAS exome

AF:

0.0158

Gnomad FIN exome

AF:

0.00131

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00662

GnomAD4 exome

AF:

0.0100

AC:

10995

AN:

1096245

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

3789

AN XY:

361675

show subpopulations

Gnomad4 AFR exome

AF:

0.00163

Gnomad4 AMR exome

AF:

0.00267

Gnomad4 ASJ exome

AF:

0.00578

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0165

Gnomad4 FIN exome

AF:

0.00178

Gnomad4 NFE exome

AF:

0.0110

Gnomad4 OTH exome

AF:

0.00836

GnomAD4 genome

AF:

0.00676

AC:

759

AN:

112314

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

200

AN XY:

34480

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00491

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.0160

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.0112

Gnomad4 OTH

AF:

0.00982

Alfa

AF:

0.0107

Hom.:

500

Bravo

AF:

0.00628

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.0111

AC:

ExAC

AF:

0.00874

AC:

1061

EpiCase

AF:

0.0107

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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	Jul 05, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.0040

DANN

Benign

0.35

DEOGEN2

Benign

0.21

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.77

MutationAssessor

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.010

REVEL

Benign

0.27

Sift

Benign

0.80

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.028

MVP

0.29

MPC

0.18

ClinPred

0.0015

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.26

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

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