22-20793005-A-G

Variant names:

• chr22-20793005-A-G
• rs165793
• NM_058004.4:c.2328+188T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_058004.4(PI4KA):​c.2328+188T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 152,056 control chromosomes in the GnomAD database, including 48,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.80 (48466 hom., cov: 31)
• Consequence: PI4KA NM_058004.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.72
• Publications: 12 publications found

Genes affected

PI4KA (HGNC:8983): (phosphatidylinositol 4-kinase alpha) This gene encodes a phosphatidylinositol (PI) 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. The protein encoded by this gene is a type III enzyme that is not inhibited by adenosine. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2018]

PI4KA Gene-Disease associations (from GenCC):

• polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 22-20793005-A-G is Benign according to our data. Variant chr22-20793005-A-G is described in ClinVar as Benign. ClinVar VariationId is 1222163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PI4KA	NM_058004.4	c.2328+188T>C		intron_variant	Intron 19 of 54	ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PI4KA	ENST00000255882.11	c.2328+188T>C		intron_variant	Intron 19 of 54	1	NM_058004.4	ENSP00000255882.6
PI4KA	ENST00000466162.5	n.91+188T>C		intron_variant	Intron 2 of 6	4
PI4KA	ENST00000484220.1	n.64+188T>C		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120838 AN: 151938 Hom.: 48428 Cov.: 31

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.797

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

GnomAD4 genome AF: 0.795 AC: 120933 AN: 152056 Hom.: 48466 Cov.: 31 AF XY: 0.787 AC XY: 58527 AN XY: 74332

African (AFR) AF: 0.871 AC: 36144 AN: 41478

American (AMR) AF: 0.742 AC: 11335 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2539 AN: 3468

East Asian (EAS) AF: 0.635 AC: 3281 AN: 5170

South Asian (SAS) AF: 0.729 AC: 3508 AN: 4812

European-Finnish (FIN) AF: 0.685 AC: 7243 AN: 10572

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54232 AN: 67966

Other (OTH) AF: 0.797 AC: 1680 AN: 2108

Alfa AF: 0.792 Hom.: 124552

Bravo AF: 0.804

Asia WGS AF: 0.688 AC: 2390 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.20
DANN	Benign	0.55
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs165793; hg19: chr22-21147293;