NM_005026.5:c.1863C>T

Variant names:

• chr1-9721495-C-T
• rs151235777
• NM_005026.5:c.1863C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005026.5(PIK3CD):​c.1863C>T​(p.Tyr621Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,613,746 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (7 hom.)
• Consequence: PIK3CD NM_005026.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.541
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-9721495-C-T is Benign according to our data. Variant chr1-9721495-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.541 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.1863C>T	p.Tyr621Tyr	synonymous	Exon 15 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.1863C>T	p.Tyr621Tyr	synonymous	Exon 14 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.1860C>T	p.Tyr620Tyr	synonymous	Exon 15 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.1863C>T	p.Tyr621Tyr	synonymous	Exon 15 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.1935C>T	p.Tyr645Tyr	synonymous	Exon 14 of 23	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.2040C>T	p.Tyr680Tyr	synonymous	Exon 15 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000880 AC: 221 AN: 251100 AF XY: 0.000869

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00245 AC: 3574 AN: 1461498 Hom.: 7 Cov.: 35 AF XY: 0.00233 AC XY: 1697 AN XY: 727068

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86254

European-Finnish (FIN) AF: 0.000509 AC: 27 AN: 53082

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00303 AC: 3371 AN: 1111982

Other (OTH) AF: 0.00197 AC: 119 AN: 60384

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74440

African (AFR) AF: 0.000530 AC: 22 AN: 41548

American (AMR) AF: 0.00144 AC: 22 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00218 AC: 148 AN: 68012

Other (OTH) AF: 0.000476 AC: 1 AN: 2100

Alfa AF: 0.00188 Hom.: 2

Bravo AF: 0.00124

EpiCase AF: 0.00174

EpiControl AF: 0.00148

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.5
DANN	Benign	0.75
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151235777; hg19: chr1-9781553; COSMIC: COSV100739938; COSMIC: COSV100739938;