22-20709708-C-T

Variant names:

• chr22-20709708-C-T
• rs435091
• NM_058004.4:c.6173+200G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_058004.4(PI4KA):​c.6173+200G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.37 (5574 hom., cov: 16)
• Consequence: PI4KA NM_058004.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 1 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 Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-20709708-C-T is Benign according to our data. Variant chr22-20709708-C-T is described in ClinVar as Benign. ClinVar VariationId is 1286373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5574 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058004.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4KA	NM_058004.4	MANE Select	c.6173+200G>A		intron	N/A	NP_477352.3	P42356-1
	PI4KA	NM_001362863.2		c.6107+200G>A		intron	N/A	NP_001349792.1
	PI4KA	NM_001362862.2		c.6080+200G>A		intron	N/A	NP_001349791.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4KA	ENST00000255882.11	TSL:1 MANE Select	c.6173+200G>A		intron	N/A	ENSP00000255882.6	P42356-1
	PI4KA	ENST00000477245.5	TSL:1	n.2546+200G>A		intron	N/A
	PI4KA	ENST00000939414.1		c.6209+200G>A		intron	N/A	ENSP00000609473.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 30052 AN: 81308 Hom.: 5564 Cov.: 16

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.336

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.370 AC: 30098 AN: 81398 Hom.: 5574 Cov.: 16 AF XY: 0.362 AC XY: 14412 AN XY: 39834

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.491 AC: 9493 AN: 19352

American (AMR) AF: 0.298 AC: 2236 AN: 7508

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 527 AN: 1698

East Asian (EAS) AF: 0.331 AC: 897 AN: 2706

South Asian (SAS) AF: 0.198 AC: 518 AN: 2622

European-Finnish (FIN) AF: 0.256 AC: 1639 AN: 6406

Middle Eastern (MID) AF: 0.310 AC: 44 AN: 142

European-Non Finnish (NFE) AF: 0.359 AC: 14145 AN: 39438

Other (OTH) AF: 0.382 AC: 420 AN: 1100

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.455 Hom.: 1506

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.73
DANN	Benign	0.30
PhyloP100		-1.1
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: rs435091; hg19: chr22-21063996; COSMIC: COSV55425809; COSMIC: COSV55425809;