18-41957721-G-C

Variant names:

• chr18-41957721-G-C
• rs1979859012
• NM_002647.4:c.220G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002647.4(PIK3C3):​c.220G>C​(p.Val74Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3C3 NM_002647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52
• Publications: 0 publications found

Genes affected

PIK3C3 (HGNC:8974): (phosphatidylinositol 3-kinase catalytic subunit type 3) Enables 1-phosphatidylinositol-3-kinase activity. Involved in early endosome to late endosome transport and regulation of cytokinesis. Acts upstream of or within autophagy and protein lipidation. Located in autolysosome; late endosome; and midbody. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002647.4. 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
	PIK3C3	NM_002647.4	MANE Select	c.220G>C	p.Val74Leu	missense	Exon 2 of 25	NP_002638.2
	PIK3C3	NM_001308020.2		c.68+2362G>C		intron	N/A	NP_001294949.1	A8MYT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3C3	ENST00000262039.9	TSL:1 MANE Select	c.220G>C	p.Val74Leu	missense	Exon 2 of 25	ENSP00000262039.3	Q8NEB9
	PIK3C3	ENST00000586545.5	TSL:1	c.220G>C	p.Val74Leu	missense	Exon 2 of 4	ENSP00000465621.1	K7EKH3
	PIK3C3	ENST00000858068.1		c.220G>C	p.Val74Leu	missense	Exon 2 of 25	ENSP00000528127.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461082 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726880

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

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.0000450 AC: 2 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111748

Other (OTH) AF: 0.00 AC: 0 AN: 60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.59
Sift	Benign	0.045	D
Sift4G	Benign	0.13	T
Polyphen		0.87	P
Vest4		0.53
MutPred		0.68		Loss of MoRF binding (P = 0.0963)
MVP		0.78
MPC		0.36
ClinPred		0.95	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.50
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1979859012; hg19: chr18-39537686;