NM_005026.5:c.708G>A

Variant names:

• chr1-9716547-G-A
• rs145697393
• NM_005026.5:c.708G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005026.5(PIK3CD):​c.708G>A​(p.Pro236Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000885 in 1,608,014 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: PIK3CD NM_005026.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.63
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-9716547-G-A is Benign according to our data. Variant chr1-9716547-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000528 (768/1455708) while in subpopulation AFR AF = 0.0161 (537/33270). AF 95% confidence interval is 0.015. There are 4 homozygotes in GnomAdExome4. There are 328 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR,Unknown gene

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.708G>A	p.Pro236Pro	synonymous	Exon 6 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.708G>A	p.Pro236Pro	synonymous	Exon 5 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.708G>A	p.Pro236Pro	synonymous	Exon 6 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.708G>A	p.Pro236Pro	synonymous	Exon 6 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.708G>A	p.Pro236Pro	synonymous	Exon 5 of 23	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.708G>A	p.Pro236Pro	synonymous	Exon 6 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 654 AN: 152188 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00115 AC: 274 AN: 239114 AF XY: 0.000844

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000656

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000528 AC: 768 AN: 1455708 Hom.: 4 Cov.: 33 AF XY: 0.000453 AC XY: 328 AN XY: 724096

African (AFR) AF: 0.0161 AC: 537 AN: 33270

American (AMR) AF: 0.00132 AC: 58 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39508

South Asian (SAS) AF: 0.000152 AC: 13 AN: 85788

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52236

Middle Eastern (MID) AF: 0.00140 AC: 6 AN: 4272

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1110474

Other (OTH) AF: 0.00145 AC: 87 AN: 60022

GnomAD4 genome AF: 0.00430 AC: 655 AN: 152306 Hom.: 8 Cov.: 33 AF XY: 0.00431 AC XY: 321 AN XY: 74484

African (AFR) AF: 0.0146 AC: 607 AN: 41560

American (AMR) AF: 0.00196 AC: 30 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00211 Hom.: 0

Bravo AF: 0.00532

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.81
PhyloP100		-5.6
Mutation Taster		=99/1	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: rs145697393; hg19: chr1-9776605;