chrX-18893546-G-GTTA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4_SupportingPP5_Moderate

The NM_000292.3(PHKA2):​c.3646_3647insTAA​(p.Leu1215_Thr1216insIle) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Consequence

PHKA2
NM_000292.3 inframe_insertion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.82
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000292.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant X-18893546-G-GTTA is Pathogenic according to our data. Variant chrX-18893546-G-GTTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 841087.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PHKA2NM_000292.3 linkuse as main transcriptc.3646_3647insTAA p.Leu1215_Thr1216insIle inframe_insertion 33/33 ENST00000379942.5
PHKA2-AS1NR_029379.1 linkuse as main transcriptn.467+209_467+211dup intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PHKA2ENST00000379942.5 linkuse as main transcriptc.3646_3647insTAA p.Leu1215_Thr1216insIle inframe_insertion 33/331 NM_000292.3 P1
PHKA2-AS1ENST00000452900.5 linkuse as main transcriptn.467+209_467+211dup intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycogen storage disease IXa1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeJun 28, 2019This variant, c.3644_3646dup, results in the insertion of 1 amino acid(s) to the PHKA2 protein (p.Leu1215_Thr1216insIle), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with PHKA2-related condition (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs2047467477; hg19: chrX-18911664; API