X-18893528-T-G

Variant names:

Variant summary

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

The NM_000292.3(PHKA2):c.3665A>C(p.Tyr1222Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,210,039 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000023 ( 0 hom. 13 hem. )

Consequence

PHKA2
NM_000292.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.81

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05097395).

BP6

Variant X-18893528-T-G is Benign according to our data. Variant chrX-18893528-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2707197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18893528-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000357 (4/112057) while in subpopulation EAS AF= 0.000841 (3/3567). AF 95% confidence interval is 0.000228. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3 link	c.3665A>C	p.Tyr1222Ser	missense_variant	Exon 33 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.3665A>C	p.Tyr1222Ser	missense_variant	Exon 33 of 33	1	NM_000292.3	ENSP00000369274.4		P46019

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34174

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00112

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000708

AC:

AN:

183500

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

67926

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000794

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1097982

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363336

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000331

Gnomad4 SAS exome

AF:

0.000166

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112057

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34237

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000841

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease IXa1

Benign:1

Feb 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 26, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.051

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.34

Sift

Benign

0.18

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.21

MutPred

0.64

Gain of disorder (P = 0.0093);

MVP

0.69

MPC

0.31

ClinPred

0.073

GERP RS

5.9

Varity_R

0.37

gMVP

0.60

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