4-25255065-A-G

Position:

• chr4-25255065-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018323.4(PI4K2B):​c.424A>G​(p.Lys142Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000344 in 1,454,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PI4K2B NM_018323.4 missense, splice_region
• Scores: Splicing: ADA: 0.001343
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.21

Genes affected

PI4K2B (HGNC:18215): (phosphatidylinositol 4-kinase type 2 beta) This gene encodes a member of the type II PI4 kinase protein family. The encoded protein is primarily cytosolic and contributes to overall PI4-kinase activity along with other protein family members. This protein is involved in early T cell activation. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36807117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PI4K2B	NM_018323.4	c.424A>G	p.Lys142Glu	missense_variant, splice_region_variant	3/10	ENST00000264864.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PI4K2B	ENST00000264864.8	c.424A>G	p.Lys142Glu	missense_variant, splice_region_variant	3/10	1	NM_018323.4
PI4K2B	ENST00000512921.4	c.136A>G	p.Lys46Glu	missense_variant, splice_region_variant	3/10	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249764 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454852 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 724234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.014
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.36
Sift	Benign	0.23	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.080	.;B
Vest4		0.49
MutPred		0.46		.;Loss of methylation at K142 (P = 0.0011);
MVP		0.73
MPC		0.47
ClinPred		0.82	D
GERP RS		5.0
Varity_R		0.36
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.13
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

LitVar

Other links and lift over

dbSNP: rs1449815548; hg19: chr4-25256687;