1-9716517-A-G

Variant names:

• chr1-9716517-A-G
• rs2230735
• NM_005026.5:c.678A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005026.5(PIK3CD):​c.678A>G​(p.Thr226Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,610,348 control chromosomes in the GnomAD database, including 574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (233 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (341 hom.)
• Consequence: PIK3CD NM_005026.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.09
• Publications: 10 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• immunodeficiency 14b, autosomal recessive

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-9716517-A-G is Benign according to our data. Variant chr1-9716517-A-G is described in ClinVar as Benign. ClinVar VariationId is 474033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

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.678A>G	p.Thr226Thr	synonymous	Exon 6 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.678A>G	p.Thr226Thr	synonymous	Exon 5 of 23	NP_001424475.1
	PIK3CD	NM_001350234.2		c.678A>G	p.Thr226Thr	synonymous	Exon 6 of 24	NP_001337163.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.678A>G	p.Thr226Thr	synonymous	Exon 6 of 24	ENSP00000366563.4
	PIK3CD	ENST00000361110.6	TSL:1	c.678A>G	p.Thr226Thr	synonymous	Exon 5 of 23	ENSP00000354410.2
	PIK3CD	ENST00000892288.1		c.678A>G	p.Thr226Thr	synonymous	Exon 6 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5577 AN: 152170 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0429

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0182 AC: 4479 AN: 246058 AF XY: 0.0151

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.0419

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.00753 AC: 10982 AN: 1458060 Hom.: 341 Cov.: 33 AF XY: 0.00710 AC XY: 5148 AN XY: 725350

African (AFR) AF: 0.113 AC: 3787 AN: 33396

American (AMR) AF: 0.0198 AC: 885 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26118

East Asian (EAS) AF: 0.0513 AC: 2036 AN: 39684

South Asian (SAS) AF: 0.00453 AC: 390 AN: 86152

European-Finnish (FIN) AF: 0.0373 AC: 1941 AN: 52094

Middle Eastern (MID) AF: 0.0191 AC: 81 AN: 4234

European-Non Finnish (NFE) AF: 0.000979 AC: 1088 AN: 1111638

Other (OTH) AF: 0.0128 AC: 768 AN: 60076

GnomAD4 genome AF: 0.0367 AC: 5596 AN: 152288 Hom.: 233 Cov.: 33 AF XY: 0.0381 AC XY: 2835 AN XY: 74460

African (AFR) AF: 0.106 AC: 4395 AN: 41560

American (AMR) AF: 0.0196 AC: 300 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0430 AC: 222 AN: 5164

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4830

European-Finnish (FIN) AF: 0.0412 AC: 438 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 68012

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0166 Hom.: 51

Bravo AF: 0.0400

Asia WGS AF: 0.0290 AC: 99 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.53
PhyloP100		-5.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2230735; hg19: chr1-9776575; COSMIC: COSV100739991; COSMIC: COSV100739991;