1-9723152-C-T

Variant names:

• chr1-9723152-C-T
• rs140234838
• NM_005026.5:c.2454C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_005026.5(PIK3CD):​c.2454C>T​(p.Thr818Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: PIK3CD NM_005026.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.98
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-9723152-C-T is Benign according to our data. Variant chr1-9723152-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 541088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.98 with no splicing effect.

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.2454C>T	p.Thr818Thr	synonymous	Exon 20 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.2454C>T	p.Thr818Thr	synonymous	Exon 19 of 23	NP_001424475.1
	PIK3CD	NM_001350234.2		c.2451C>T	p.Thr817Thr	synonymous	Exon 20 of 24	NP_001337163.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.2454C>T	p.Thr818Thr	synonymous	Exon 20 of 24	ENSP00000366563.4
	PIK3CD	ENST00000361110.6	TSL:1	c.2526C>T	p.Thr842Thr	synonymous	Exon 19 of 23	ENSP00000354410.2
	PIK3CD	ENST00000698712.1		c.2454C>T	p.Thr818Thr	synonymous	Exon 19 of 23	ENSP00000513889.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000955 AC: 24 AN: 251394 AF XY: 0.0000736

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1461424 Hom.: 0 Cov.: 32 AF XY: 0.0000990 AC XY: 72 AN XY: 727038

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 52984

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1111986

Other (OTH) AF: 0.000132 AC: 8 AN: 60390

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74468

African (AFR) AF: 0.000337 AC: 14 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000264

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 14 (1)
-	-	1	not specified (1)
-	-	1	PIK3CD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.2
DANN	Benign	0.65
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs140234838; hg19: chr1-9783210; COSMIC: COSV63127357;