rs149219369

Positions:

• chrX-18941651-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000292.3(PHKA2):​c.742A>C​(p.Arg248=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,172,943 control chromosomes in the GnomAD database, including 3 homozygotes. There are 602 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 0.0013 (0 hom., 42 hem., cov: 23)
  • Exomes 𝑓: 0.0018 (3 hom. 560 hem.)
• Consequence: PHKA2 NM_000292.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-18941651-T-G is Benign according to our data. Variant chrX-18941651-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 198712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18941651-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0013 (147/113213) while in subpopulation NFE AF= 0.0023 (123/53430). AF 95% confidence interval is 0.00197. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 42 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3	c.742A>C	p.Arg248=	synonymous_variant	8/33	ENST00000379942.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5	c.742A>C	p.Arg248=	synonymous_variant	8/33	1	NM_000292.3	P1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 147 AN: 113213 Hom.: 0 Cov.: 23 AF XY: 0.00119 AC XY: 42 AN XY: 35341

Gnomad AFR AF: 0.000416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000747

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00230

Gnomad OTH AF: 0.00197

GnomAD3 exomes AF: 0.00119 AC: 219 AN: 183338 Hom.: 1 AF XY: 0.00114 AC XY: 77 AN XY: 67782

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00235

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.00184 AC: 1949 AN: 1059730 Hom.: 3 Cov.: 25 AF XY: 0.00170 AC XY: 560 AN XY: 330144

Gnomad4 AFR exome AF: 0.000117

Gnomad4 AMR exome AF: 0.000654

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000375

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00130 AC: 147 AN: 113213 Hom.: 0 Cov.: 23 AF XY: 0.00119 AC XY: 42 AN XY: 35341

Gnomad4 AFR AF: 0.000416

Gnomad4 AMR AF: 0.000747

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00230

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.00189 Hom.: 13

Bravo AF: 0.00137

EpiCase AF: 0.00229

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2018	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	Eurofins Ntd Llc (ga)	Feb 23, 2015	- -

Glycogen storage disease IXa1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.1
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs149219369; hg19: chrX-18959769; COSMIC: COSV66054365;