22-20710808-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_058004.4(PI4KA):​c.5974C>T​(p.Pro1992Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

PI4KA
NM_058004.4 missense

Scores

6
6
6

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.65
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.783
PP5
Variant 22-20710808-G-A is Pathogenic according to our data. Variant chr22-20710808-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1675874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PI4KANM_058004.4 linkc.5974C>T p.Pro1992Ser missense_variant Exon 52 of 55 ENST00000255882.11 NP_477352.3 P42356-1Q4LE69B4DYG5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PI4KAENST00000255882.11 linkc.5974C>T p.Pro1992Ser missense_variant Exon 52 of 55 1 NM_058004.4 ENSP00000255882.6 P42356-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin BerlinSep 16, 2022- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
D;.
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.021
T
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Benign
-1.1
T
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.6
.;D
REVEL
Uncertain
0.41
Sift
Benign
0.10
.;T
Sift4G
Benign
0.068
T;T
Polyphen
0.97
.;D
Vest4
0.84
MVP
0.57
MPC
2.5
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.48
gMVP
0.79

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-21065096; API