18-41962608-C-A

Variant names:

• chr18-41962608-C-A
• rs778669649
• NM_002647.4:c.377C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002647.4(PIK3C3):​c.377C>A​(p.Thr126Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T126M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIK3C3 NM_002647.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.70
• Publications: 2 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

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.377C>A	p.Thr126Lys	missense	Exon 3 of 25	NP_002638.2
	PIK3C3	NM_001308020.2		c.188C>A	p.Thr63Lys	missense	Exon 2 of 24	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.377C>A	p.Thr126Lys	missense	Exon 3 of 25	ENSP00000262039.3	Q8NEB9
	PIK3C3	ENST00000586545.5	TSL:1	c.377C>A	p.Thr126Lys	missense	Exon 3 of 4	ENSP00000465621.1	K7EKH3
	PIK3C3	ENST00000858068.1		c.377C>A	p.Thr126Lys	missense	Exon 3 of 25	ENSP00000528127.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249492 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458580 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725646

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109928

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.69	P
Vest4		0.93
MutPred		0.78		Gain of ubiquitination at T126 (P = 0.0311)
MVP		0.85
MPC		0.82
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
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

Other links and lift over

dbSNP: rs778669649; hg19: chr18-39542573;