X-18893636-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000292.3(PHKA2):c.3557A>C(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 𝑓: 0.0000046 (0 hom. 5 hem.)
• Consequence: PHKA2 NM_000292.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.32

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)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1838752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.3557A>C	p.Asp1186Ala	missense_variant	33/33	ENST00000379942.5
PHKA2-AS1	NR_029379.1	n.467+298T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.3557A>C	p.Asp1186Ala	missense_variant	33/33	1	NM_000292.3	P1
PHKA2-AS1	ENST00000452900.5	n.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

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

Submissions by phenotype

Glycogen storage disease IXa1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Nov 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;