Variant X-18893591-TAAA-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000292.3(PHKA2):c.3599_3601del(p.Phe1200del) variant causes a inframe deletion change involving the alteration of a 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: 23)

Consequence

PHKA2
NM_000292.3 inframe_deletion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.89

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 links:

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

PHKA2-AS1 links:

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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-18893591-TAAA-T is Pathogenic according to our data. Variant chrX-18893591-TAAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420714.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHKA2	NM_000292.3 linkuse as main transcript	c.3599_3601del	p.Phe1200del	inframe_deletion	33/33	ENST00000379942.5
PHKA2-AS1	NR_029379.1 linkuse as main transcript	n.467+255_467+257del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHKA2	ENST00000379942.5 linkuse as main transcript	c.3599_3601del	p.Phe1200del	inframe_deletion	33/33	1	NM_000292.3	P1
PHKA2-AS1	ENST00000452900.5 linkuse as main transcript	n.467+255_467+257del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2018

The c.3599_3601delTTT variant in the PHKA2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.3599_3601delTTT variant is an in-frame deletion that results in the loss of a single Phenylalanine residue, denoted p.Phe1200del. The residue removed by this deletion is conserved across species. In silico analysis predicts this deletion is probably damaging to the protein structure/function. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3599_3601delTTT as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing