rs140662042

Positions:

chrX-18941678-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000292.3(PHKA2):c.718-3C>T variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0151 in 1,157,524 control chromosomes in the GnomAD database, including 121 homozygotes. There are 4,958 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 8 hom., 352 hem., cov: 23)

Exomes 𝑓: 0.016 ( 113 hom. 4606 hem. )

Consequence

PHKA2
NM_000292.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.01200

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.62

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant X-18941678-G-A is Benign according to our data. Variant chrX-18941678-G-A is described in ClinVar as [Benign]. Clinvar id is 255778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18941678-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1284/113254) while in subpopulation NFE AF= 0.0198 (1055/53403). AF 95% confidence interval is 0.0188. There are 8 homozygotes in gnomad4. There are 352 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHKA2	NM_000292.3 linkuse as main transcript	c.718-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		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.718-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000292.3	ENSP00000369274	P1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1285

AN:

113202

Hom.:

Cov.:

AF XY:

0.00996

AC XY:

352

AN XY:

35350

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.0189

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00563

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000710

Gnomad FIN

AF:

0.00651

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0198

Gnomad OTH

AF:

0.00982

GnomAD3 exomes

AF:

0.0101

AC:

1845

AN:

183016

Hom.:

AF XY:

0.00984

AC XY:

665

AN XY:

67550

show subpopulations

Gnomad AFR exome

AF:

0.00244

Gnomad AMR exome

AF:

0.00401

Gnomad ASJ exome

AF:

0.00803

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00184

Gnomad FIN exome

AF:

0.00632

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.00907

GnomAD4 exome

AF:

0.0155

AC:

16220

AN:

1044270

Hom.:

113

Cov.:

AF XY:

0.0144

AC XY:

4606

AN XY:

320118

show subpopulations

Gnomad4 AFR exome

AF:

0.00220

Gnomad4 AMR exome

AF:

0.00438

Gnomad4 ASJ exome

AF:

0.00756

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00230

Gnomad4 FIN exome

AF:

0.00746

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0137

GnomAD4 genome

AF:

0.0113

AC:

1284

AN:

113254

Hom.:

Cov.:

AF XY:

0.00994

AC XY:

352

AN XY:

35412

show subpopulations

Gnomad4 AFR

AF:

0.00265

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.00563

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000712

Gnomad4 FIN

AF:

0.00651

Gnomad4 NFE

AF:

0.0198

Gnomad4 OTH

AF:

0.00971

Alfa

AF:

0.0165

Hom.:

130

Bravo

AF:

0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.060

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