chr7-106867982-C-A

Variant names:

• chr7-106867982-C-A
• rs367817179
• NM_001282426.2:c.421C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001282426.2(PIK3CG):​c.421C>A​(p.His141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PIK3CG NM_001282426.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• Publications: 1 publications found

Genes affected

PIK3CG (HGNC:8978): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma) Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I catalytic subunit of PI3K. Like other class I catalytic subunits (p110-alpha p110-beta, and p110-delta), the encoded protein binds a p85 regulatory subunit to form PI3K. This gene is located in a commonly deleted segment of chromosome 7 previously identified in myeloid leukemias. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2015]

PIK3CG Gene-Disease associations (from GenCC):

• immunodeficiency 97 with autoinflammation

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037754804).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282426.2. 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
	PIK3CG	NM_001282426.2	MANE Select	c.421C>A	p.His141Asn	missense	Exon 2 of 11	NP_001269355.1	P48736
	PIK3CG	NM_001282427.2		c.421C>A	p.His141Asn	missense	Exon 2 of 11	NP_001269356.1	P48736
	PIK3CG	NM_002649.3		c.421C>A	p.His141Asn	missense	Exon 2 of 11	NP_002640.2	P48736

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CG	ENST00000496166.6	TSL:1 MANE Select	c.421C>A	p.His141Asn	missense	Exon 2 of 11	ENSP00000419260.1	P48736
	PIK3CG	ENST00000359195.3	TSL:1	c.421C>A	p.His141Asn	missense	Exon 2 of 11	ENSP00000352121.3	P48736
	PIK3CG	ENST00000440650.6	TSL:1	c.421C>A	p.His141Asn	missense	Exon 2 of 11	ENSP00000392258.2	P48736

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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

GnomAD2 exomes AF: 0.0000244 AC: 6 AN: 245556 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459920 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726110

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111204

Other (OTH) AF: 0.0000497 AC: 3 AN: 60302

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.079
Sift	Benign	0.30	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.18		Loss of disorder (P = 0.08)
MVP		0.34
MPC		0.46
ClinPred		0.027	T
GERP RS		3.7
Varity_R		0.091
gMVP		0.14
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs367817179; hg19: chr7-106508427;