chr1-9715845-G-C

Variant names:

• chr1-9715845-G-C
• rs775036315
• NM_005026.5:c.371-4G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005026.5(PIK3CD):​c.371-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3CD NM_005026.5 splice_region, intron
• Scores: Splicing: ADA: 0.000008829
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.371-4G>C		splice_region intron	N/A	NP_005017.3
	PIK3CD	NM_001437546.1		c.371-4G>C		splice_region intron	N/A	NP_001424475.1
	PIK3CD	NM_001350234.2		c.371-4G>C		splice_region 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.371-4G>C		splice_region intron	N/A	ENSP00000366563.4
	PIK3CD	ENST00000361110.6	TSL:1	c.371-4G>C		splice_region intron	N/A	ENSP00000354410.2
	PIK3CD	ENST00000698717.1		n.5G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000141 AC: 2 AN: 141822 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000243

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000877 AC: 44 AN: 501820 Hom.: 0 Cov.: 24 AF XY: 0.0000549 AC XY: 15 AN XY: 273244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000671 AC: 1 AN: 14910

American (AMR) AF: 0.00 AC: 0 AN: 37100

Ashkenazi Jewish (ASJ) AF: 0.0000763 AC: 1 AN: 13106

East Asian (EAS) AF: 0.0000655 AC: 1 AN: 15274

South Asian (SAS) AF: 0.00 AC: 0 AN: 69030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3192

European-Non Finnish (NFE) AF: 0.000129 AC: 38 AN: 294586

Other (OTH) AF: 0.000139 AC: 3 AN: 21572

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000141 AC: 2 AN: 141928 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 68884

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000251 AC: 1 AN: 39828

American (AMR) AF: 0.00 AC: 0 AN: 14506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3300

East Asian (EAS) AF: 0.000243 AC: 1 AN: 4110

South Asian (SAS) AF: 0.00 AC: 0 AN: 3902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64398

Other (OTH) AF: 0.00 AC: 0 AN: 2018

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.011
DANN	Benign	0.42
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000088
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.050		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: rs775036315; hg19: chr1-9775903;