Genetic Variant NM_005026.5:c.2698A>G (chr1-9724072-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005026.5(PIK3CD):c.2698A>G(p.Met900Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PIK3CD
NM_005026.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Publications

0 publications found

Variant links:

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

PIK3CD links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3CD	NM_005026.5	MANE Select	c.2698A>G	p.Met900Val	missense	Exon 21 of 24	NP_005017.3
PIK3CD	NM_001437546.1		c.2698A>G	p.Met900Val	missense	Exon 20 of 23	NP_001424475.1	A0A2K8FKV1
PIK3CD	NM_001350234.2		c.2695A>G	p.Met899Val	missense	Exon 21 of 24	NP_001337163.1	B7ZM44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIK3CD	ENST00000377346.9	TSL:1 MANE Select	c.2698A>G	p.Met900Val	missense	Exon 21 of 24	ENSP00000366563.4	O00329-1
PIK3CD	ENST00000361110.6	TSL:1	c.2770A>G	p.Met924Val	missense	Exon 20 of 23	ENSP00000354410.2	F8W9P4
PIK3CD	ENST00000892288.1		c.2875A>G	p.Met959Val	missense	Exon 21 of 24	ENSP00000562347.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 14 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.4

PhyloP100

9.3

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.89

Loss of disorder (P = 0.0941)

MVP

0.93

MPC

1.1

ClinPred

1.0

GERP RS

4.9

Varity_R

0.98

gMVP

0.99

Mutation Taster

=40/60

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over