X-18893628-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000292.3(PHKA2):c.3565G>A(p.Glu1189Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000628 in 1,210,198 control chromosomes in the GnomAD database, including 1 homozygotes. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. E1189E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000068 ( 1 hom. 44 hem. )

Consequence

PHKA2
NM_000292.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.52

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:

PHKA2-AS1 (HGNC:44110): (PHKA2 antisense RNA 1)

PHKA2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03981325).

BP6

Variant X-18893628-C-T is Benign according to our data. Variant chrX-18893628-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3061037.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000683 (75/1097615) while in subpopulation SAS AF= 0.00139 (75/54135). AF 95% confidence interval is 0.00113. There are 1 homozygotes in gnomad4_exome. There are 44 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3 linkuse as main transcript	c.3565G>A	p.Glu1189Lys	missense_variant	33/33	ENST00000379942.5
PHKA2-AS1	NR_029379.1 linkuse as main transcript	n.467+290C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5 linkuse as main transcript	c.3565G>A	p.Glu1189Lys	missense_variant	33/33	1	NM_000292.3	P1
PHKA2-AS1	ENST00000452900.5 linkuse as main transcript	n.467+290C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112583

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34733

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000366

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

182425

Hom.:

AF XY:

0.000356

AC XY:

AN XY:

67383

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00194

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000683

AC:

AN:

1097615

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

362981

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112583

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34733

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000366

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PHKA2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.38

Sift

Benign

0.44

Sift4G

Benign

0.30

Polyphen

0.0060

Vest4

0.17

MutPred

0.50

Gain of ubiquitination at E1189 (P = 0.0117);

MVP

0.68

MPC

0.25

ClinPred

0.21

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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