chr1-9717528-G-C

Variant names:

• chr1-9717528-G-C
• rs28730669
• NM_005026.5:c.931-9G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005026.5(PIK3CD):​c.931-9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,613,626 control chromosomes in the GnomAD database, including 497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (24 hom., cov: 32)
  • Exomes 𝑓: 0.023 (473 hom.)
• Consequence: PIK3CD NM_005026.5 intron
• Scores: Splicing: ADA: 0.00002334
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0980
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-9717528-G-C is Benign according to our data. Variant chr1-9717528-G-C is described in ClinVar as Benign. ClinVar VariationId is 440067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0169 (2575/152294) while in subpopulation NFE AF = 0.0248 (1686/68018). AF 95% confidence interval is 0.0238. There are 24 homozygotes in GnomAd4. There are 1223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	NM_005026.5	MANE Select	c.931-9G>C		intron	N/A	NP_005017.3
	PIK3CD	NM_001437546.1		c.931-9G>C		intron	N/A	NP_001424475.1
	PIK3CD	NM_001350234.2		c.931-9G>C		intron	N/A	NP_001337163.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.931-9G>C		intron	N/A	ENSP00000366563.4
	PIK3CD	ENST00000361110.6	TSL:1	c.826-9G>C		intron	N/A	ENSP00000354410.2
	PIK3CD	ENST00000698786.1		n.33G>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2575 AN: 152176 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0170 AC: 4255 AN: 249950 AF XY: 0.0166

Gnomad AFR exome AF: 0.00469

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0227 AC: 33118 AN: 1461332 Hom.: 473 Cov.: 32 AF XY: 0.0218 AC XY: 15821 AN XY: 726996

African (AFR) AF: 0.00353 AC: 118 AN: 33472

American (AMR) AF: 0.0177 AC: 793 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 439 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86254

European-Finnish (FIN) AF: 0.0258 AC: 1373 AN: 53224

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5756

European-Non Finnish (NFE) AF: 0.0262 AC: 29118 AN: 1111704

Other (OTH) AF: 0.0202 AC: 1219 AN: 60374

GnomAD4 genome AF: 0.0169 AC: 2575 AN: 152294 Hom.: 24 Cov.: 32 AF XY: 0.0164 AC XY: 1223 AN XY: 74468

African (AFR) AF: 0.00447 AC: 186 AN: 41570

American (AMR) AF: 0.0226 AC: 345 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.0231 AC: 245 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0248 AC: 1686 AN: 68018

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0207 Hom.: 8

Bravo AF: 0.0167

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0229

EpiControl AF: 0.0231

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Immunodeficiency 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.59
PhyloP100		-0.098
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs28730669; hg19: chr1-9777586;