rs557471275

Variant names:

• chr1-9717032-T-C
• rs557471275
• NM_005026.5:c.854T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005026.5(PIK3CD):​c.854T>C​(p.Met285Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M285K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 2.65
• Publications: 5 publications found

Genes affected

PIK3CD (HGNC:8977): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I PI3K found primarily in leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, and p110-gamma), the encoded protein binds p85 adapter proteins and GTP-bound RAS. However, unlike the other class I PI3Ks, this protein phosphorylates itself, not p85 protein.[provided by RefSeq, Jul 2010]

PIK3CD Gene-Disease associations (from GenCC):

• immunodeficiency 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• immunodeficiency 14b, autosomal recessive

  Inheritance: Unknown, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122813314).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005026.5. 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
	PIK3CD	NM_005026.5	MANE Select	c.854T>C	p.Met285Thr	missense	Exon 7 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.854T>C	p.Met285Thr	missense	Exon 6 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.854T>C	p.Met285Thr	missense	Exon 7 of 24	NP_001337163.1	B7ZM44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.854T>C	p.Met285Thr	missense	Exon 7 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.781-32T>C		intron	N/A	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.854T>C	p.Met285Thr	missense	Exon 7 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 251356 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461600 Hom.: 0 Cov.: 33 AF XY: 0.000118 AC XY: 86 AN XY: 727104

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1111960

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74458

African (AFR) AF: 0.0000963 AC: 4 AN: 41536

American (AMR) AF: 0.000654 AC: 10 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000193 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Activated PI3K-delta syndrome (1)
-	1	-	Immunodeficiency 14 (1)
-	1	-	not provided (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0028
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.071
Sift	Benign	0.29	T
Sift4G	Benign	0.40	T
Polyphen		0.24	B
Vest4		0.53
MVP		0.51
MPC		1.1
ClinPred		0.054	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.66
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs557471275; hg19: chr1-9777090; COSMIC: COSV63128813; COSMIC: COSV63128813;