rs143068130

Variant names:

• chr1-9721214-G-C
• rs143068130
• NM_005026.5:c.1777G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005026.5(PIK3CD):​c.1777G>C​(p.Gly593Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,613,342 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 (★★). The gene PIK3CD is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 5.23
• Publications: 18 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

Specifications for PIK3CD are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05640745).

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.1777G>C	p.Gly593Arg	missense	Exon 14 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.1777G>C	p.Gly593Arg	missense	Exon 13 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.1774G>C	p.Gly592Arg	missense	Exon 14 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.1777G>C	p.Gly593Arg	missense	Exon 14 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.1849G>C	p.Gly617Arg	missense	Exon 13 of 23	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.1954G>C	p.Gly652Arg	missense	Exon 14 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251102 AF XY: 0.0000957

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000245 AC: 358 AN: 1461144 Hom.: 0 Cov.: 35 AF XY: 0.000256 AC XY: 186 AN XY: 726926

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000247 AC: 13 AN: 52736

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

European-Non Finnish (NFE) AF: 0.000299 AC: 332 AN: 1111974

Other (OTH) AF: 0.000132 AC: 8 AN: 60382

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74346

African (AFR) AF: 0.0000965 AC: 4 AN: 41456

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Activated PI3K-delta syndrome (1)
-	1	-	Combined immunodeficiency with faciooculoskeletal anomalies;C3714976:Immunodeficiency 14;C5543301:Immunodeficiency 14b, autosomal recessive (1)
-	1	-	Immunodeficiency 14 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-2.0	N
PhyloP100		5.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	3.3	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.17	B
Vest4		0.31
MVP		0.15
MPC		1.3
ClinPred		0.088	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.58
Mutation Taster		=45/55	disease causing

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: rs143068130; hg19: chr1-9781272;