X-18901437-G-T

Variant names:

• chrX-18901437-G-T
• rs201339926
• NM_000292.3:c.3027+48C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000292.3(PHKA2):​c.3027+48C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 837,108 control chromosomes in the GnomAD database, including 3 homozygotes. There are 322 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 0.0011 (0 hom., 26 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (3 hom. 296 hem.)
• Consequence: PHKA2 NM_000292.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.95

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-18901437-G-T is Benign according to our data. Variant chrX-18901437-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00109 (121/111282) while in subpopulation AMR AF= 0.002 (21/10485). AF 95% confidence interval is 0.00134. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA2	NM_000292.3	c.3027+48C>A		intron_variant	Intron 27 of 32	ENST00000379942.5	NP_000283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA2	ENST00000379942.5	c.3027+48C>A		intron_variant	Intron 27 of 32	1	NM_000292.3	ENSP00000369274.4
PHKA2	ENST00000469645.5	n.511+48C>A		intron_variant	Intron 5 of 6	5
PHKA2	ENST00000473739.5	n.119+48C>A		intron_variant	Intron 1 of 5	3
PHKA2	ENST00000486231.2	n.296+48C>A		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 121 AN: 111230 Hom.: 0 Cov.: 22 AF XY: 0.000778 AC XY: 26 AN XY: 33404

Gnomad AFR AF: 0.000294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00201

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000385

Gnomad FIN AF: 0.000334

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.00136

Gnomad OTH AF: 0.00533

GnomAD3 exomes AF: 0.00124 AC: 226 AN: 182535 Hom.: 0 AF XY: 0.00134 AC XY: 90 AN XY: 67097

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000472

Gnomad FIN exome AF: 0.000391

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00119 AC: 864 AN: 725826 Hom.: 3 Cov.: 12 AF XY: 0.00139 AC XY: 296 AN XY: 212428

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.00275

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000576

Gnomad4 FIN exome AF: 0.000578

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00109 AC: 121 AN: 111282 Hom.: 0 Cov.: 22 AF XY: 0.000777 AC XY: 26 AN XY: 33466

Gnomad4 AFR AF: 0.000294

Gnomad4 AMR AF: 0.00200

Gnomad4 ASJ AF: 0.00227

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000386

Gnomad4 FIN AF: 0.000334

Gnomad4 NFE AF: 0.00136

Gnomad4 OTH AF: 0.00526

Alfa AF: 0.00109 Hom.: 7

Bravo AF: 0.00122

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs201339926; hg19: chrX-18919555;