chrX-18893636-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000292.3(PHKA2):ā€‹c.3557A>Cā€‹(p.Asp1186Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,315 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 24)
Exomes š‘“: 0.0000046 ( 0 hom. 5 hem. )

Consequence

PHKA2
NM_000292.3 missense

Scores

4
13

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.32
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-AS1 (HGNC:44110): (PHKA2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1838752).
BS2
High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PHKA2NM_000292.3 linkuse as main transcriptc.3557A>C p.Asp1186Ala missense_variant 33/33 ENST00000379942.5
PHKA2-AS1NR_029379.1 linkuse as main transcriptn.467+298T>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PHKA2ENST00000379942.5 linkuse as main transcriptc.3557A>C p.Asp1186Ala missense_variant 33/331 NM_000292.3 P1
PHKA2-AS1ENST00000452900.5 linkuse as main transcriptn.467+298T>G intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
0.00000456
AC:
5
AN:
1097315
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
5
AN XY:
362685
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000594
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Glycogen storage disease IXa1 Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.027
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
T
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.75
T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
1.4
L
MutationTaster
Benign
0.95
D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.36
Sift
Benign
0.33
T
Sift4G
Benign
0.63
T
Polyphen
0.0010
B
Vest4
0.22
MutPred
0.56
Loss of helix (P = 0.0558);
MVP
0.67
MPC
0.28
ClinPred
0.22
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-18911754; API