10-97651134-G-A

Variant names:

• chr10-97651134-G-A
• rs184615614
• NM_018425.4:c.629G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_018425.4(PI4K2A):​c.629G>A​(p.Arg210His) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,611,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PI4K2A NM_018425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67
• Publications: 2 publications found

Genes affected

PI4K2A (HGNC:30031): (phosphatidylinositol 4-kinase type 2 alpha) Phosphatidylinositolpolyphosphates (PtdInsPs) are centrally involved in many biologic processes, ranging from cell growth and organization of the actin cytoskeleton to endo- and exocytosis. PI4KII phosphorylates PtdIns at the D-4 position, an essential step in the biosynthesis of PtdInsPs (Barylko et al., 2001 [PubMed 11244087]).[supplied by OMIM, Mar 2008]

ENSG00000249967 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29207706).
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018425.4. 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
	PI4K2A	NM_018425.4	MANE Select	c.629G>A	p.Arg210His	missense	Exon 2 of 9	NP_060895.1	Q9BTU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PI4K2A	ENST00000370631.4	TSL:1 MANE Select	c.629G>A	p.Arg210His	missense	Exon 2 of 9	ENSP00000359665.3	Q9BTU6
	ENSG00000249967	ENST00000370649.3	TSL:2	c.539G>A	p.Arg180His	missense	Exon 3 of 10	ENSP00000359683.3	E9PAM4
	PI4K2A	ENST00000880060.1		c.629G>A	p.Arg210His	missense	Exon 2 of 10	ENSP00000550119.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251292 AF XY: 0.0000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000254 AC: 37 AN: 1459324 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 726098

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.000279 AC: 24 AN: 86170

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110828

Other (OTH) AF: 0.00 AC: 0 AN: 60220

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74446

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00383038), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.35
Sift	Benign	0.28	T
Sift4G	Benign	0.082	T
Polyphen		0.91	P
Vest4		0.43
MVP		0.58
MPC		2.1
ClinPred		0.38	T
GERP RS		3.1
Varity_R		0.16
gMVP		0.79
Mutation Taster		=74/26	polymorphism

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: rs184615614; hg19: chr10-99410891; COSMIC: COSV65701797;