X-18929306-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_000292.3(PHKA2):c.1246G>A(p.Gly416Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,137,319 control chromosomes in the GnomAD database, including 5 homozygotes. There are 288 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 1 hom., 151 hem., cov: 24)

Exomes 𝑓: 0.00049 ( 4 hom. 137 hem. )

Consequence

PHKA2
NM_000292.3 missense, splice_region

Scores

Splicing: ADA: 0.9761

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 7.67

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 was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant X-18929306-C-T is Benign according to our data. Variant chrX-18929306-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 506571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0048 (538/112152) while in subpopulation AFR AF = 0.0166 (514/30899). AF 95% confidence interval is 0.0154. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position FAILED quality control check.

BS2

High Hemizygotes in GnomAd4 at 151 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3 link	c.1246G>A	p.Gly416Arg	missense_variant, splice_region_variant	Exon 13 of 33	ENST00000379942.5	NP_000283.1	P46019

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5 link	c.1246G>A	p.Gly416Arg	missense_variant, splice_region_variant	Exon 13 of 33	1	NM_000292.3	ENSP00000369274.4		P46019

Frequencies

GnomAD3 genomes

AF:

0.00479

AC:

537

AN:

112098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00330

GnomAD2 exomes

AF:

0.00147

AC:

189

AN:

128158

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.00152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000592

Gnomad OTH exome

AF:

0.00166

GnomAD4 exome

AF:

0.000489

AC:

501

AN:

1025167

Hom.:

Cov.:

AF XY:

0.000436

AC XY:

137

AN XY:

313907

show subpopulations

Gnomad4 AFR exome

AF:

0.0156

AC:

383

AN:

24484

Gnomad4 AMR exome

AF:

0.00149

AC:

AN:

30290

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

18625

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

27831

Gnomad4 SAS exome

AF:

0.000141

AC:

AN:

49554

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

38117

Gnomad4 NFE exome

AF:

0.0000152

AC:

AN:

788779

Gnomad4 Remaining exome

AF:

0.00115

AC:

AN:

43482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00480

AC:

538

AN:

112152

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

151

AN XY:

34388

show subpopulations

Gnomad4 AFR

AF:

0.0166

AC:

0.0166348

AN:

0.0166348

Gnomad4 AMR

AF:

0.00160

AC:

0.00160347

AN:

0.00160347

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000376

AC:

0.0000375982

AN:

0.0000375982

Gnomad4 OTH

AF:

0.00326

AC:

0.00326158

AN:

0.00326158

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00178

Hom.:

110

Bravo

AF:

0.00557

ESP6500AA

AF:

0.0183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00142

AC:

152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Apr 17, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PHKA2: PP3, BS1, BS2 -

not specified

Benign:2

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.016

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

3.1

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.97

Vest4

0.71

MutPred

0.31

Gain of relative solvent accessibility (P = 0.1259);

MVP

0.75

MPC

0.91

ClinPred

0.031

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.75

Mutation Taster

=9/91

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: -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