chr22-20710731-C-G

Position:

• chr22-20710731-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_058004.4(PI4KA):​c.6051G>C​(p.Met2017Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PI4KA NM_058004.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PI4KA. . Gene score misZ 3.5271 (greater than the threshold 3.09). Trascript score misZ 4.6291 (greater than threshold 3.09). GenCC has associacion of gene with polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PI4KA	NM_058004.4	c.6051G>C	p.Met2017Ile	missense_variant	52/55	ENST00000255882.11	NP_477352.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PI4KA	ENST00000255882.11	c.6051G>C	p.Met2017Ile	missense_variant	52/55	1	NM_058004.4	ENSP00000255882.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.6051G>C (p.M2017I) alteration is located in exon 52 (coding exon 52) of the PI4KA gene. This alteration results from a G to C substitution at nucleotide position 6051, causing the methionine (M) at amino acid position 2017 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.16	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.41	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0010	.;B
Vest4		0.87
MVP		0.48
MPC		2.2
ClinPred		0.84	D
GERP RS		5.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.62
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-21065019;