chr1-9717541-C-G

Variant names:

• chr1-9717541-C-G
• rs61755420
• NM_005026.5:c.935C>G

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.935C>G​(p.Ser312Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,613,884 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S312S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (45 hom., cov: 32)
  • Exomes 𝑓: 0.027 (615 hom.)
• Consequence: PIK3CD NM_005026.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.09
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024999976).
• BP6: Variant 1-9717541-C-G is Benign according to our data. Variant chr1-9717541-C-G is described in ClinVar as Benign. ClinVar VariationId is 440066.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 = 0.0187 (2851/152378) while in subpopulation NFE AF = 0.027 (1834/68042). AF 95% confidence interval is 0.0259. There are 45 homozygotes in GnomAd4. There are 1338 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 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.935C>G	p.Ser312Cys	missense	Exon 8 of 24	NP_005017.3
	PIK3CD	NM_001437546.1		c.935C>G	p.Ser312Cys	missense	Exon 7 of 23	NP_001424475.1	A0A2K8FKV1
	PIK3CD	NM_001350234.2		c.935C>G	p.Ser312Cys	missense	Exon 8 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.935C>G	p.Ser312Cys	missense	Exon 8 of 24	ENSP00000366563.4	O00329-1
	PIK3CD	ENST00000361110.6	TSL:1	c.830C>G	p.Ser277Cys	missense	Exon 7 of 23	ENSP00000354410.2	F8W9P4
	PIK3CD	ENST00000892288.1		c.935C>G	p.Ser312Cys	missense	Exon 8 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2853 AN: 152260 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0202 AC: 5055 AN: 250332 AF XY: 0.0203

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0476

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0263

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0270 AC: 39495 AN: 1461506 Hom.: 615 Cov.: 32 AF XY: 0.0262 AC XY: 19068 AN XY: 727078

African (AFR) AF: 0.00391 AC: 131 AN: 33476

American (AMR) AF: 0.0119 AC: 533 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 1220 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00270 AC: 233 AN: 86256

European-Finnish (FIN) AF: 0.0283 AC: 1507 AN: 53270

Middle Eastern (MID) AF: 0.0175 AC: 101 AN: 5768

European-Non Finnish (NFE) AF: 0.0307 AC: 34132 AN: 1111800

Other (OTH) AF: 0.0271 AC: 1637 AN: 60384

GnomAD4 genome AF: 0.0187 AC: 2851 AN: 152378 Hom.: 45 Cov.: 32 AF XY: 0.0180 AC XY: 1338 AN XY: 74508

African (AFR) AF: 0.00507 AC: 211 AN: 41600

American (AMR) AF: 0.0155 AC: 237 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.0238 AC: 253 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1834 AN: 68042

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0281 Hom.: 21

Bravo AF: 0.0196

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0299 AC: 257

ExAC AF: 0.0207 AC: 2509

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0295

EpiControl AF: 0.0313

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Immunodeficiency 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.33
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.054	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Benign	0.042	D
Sift4G	Uncertain	0.029	D
Polyphen		0.0	B
Vest4		0.12
MPC		1.6
ClinPred		0.023	T
GERP RS		3.6
Varity_R		0.21
gMVP		0.55
Mutation Taster		=96/4	polymorphism (auto)

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: rs61755420; hg19: chr1-9777599; COSMIC: COSV104667069; COSMIC: COSV104667069;