chr5-68226826-G-C

Variant names:

• chr5-68226826-G-C
• rs2111964278
• NM_181523.3:c.151G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181523.3(PIK3R1):​c.151G>C​(p.Glu51Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E51K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3R1 NM_181523.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.84
• Publications: 0 publications found

Genes affected

PIK3R1 (HGNC:8979): (phosphoinositide-3-kinase regulatory subunit 1) Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The enzyme comprises a 110 kD catalytic subunit and a regulatory subunit of either 85, 55, or 50 kD. This gene encodes the 85 kD regulatory subunit. Phosphatidylinositol 3-kinase plays an important role in the metabolic actions of insulin, and a mutation in this gene has been associated with insulin resistance. Alternative splicing of this gene results in four transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

PIK3R1 Gene-Disease associations (from GenCC):

• immunodeficiency 36 with lymphoproliferation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• SHORT syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• agammaglobulinemia 7, autosomal recessive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16754445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.151G>C	p.Glu51Gln	missense_variant	Exon 2 of 16	ENST00000521381.6	NP_852664.1
PIK3R1	XM_005248542.4	c.151G>C	p.Glu51Gln	missense_variant	Exon 2 of 16		XP_005248599.1
PIK3R1	XM_017009585.3	c.151G>C	p.Glu51Gln	missense_variant	Exon 2 of 16		XP_016865074.1
PIK3R1	XM_047417315.1	c.151G>C	p.Glu51Gln	missense_variant	Exon 2 of 16		XP_047273271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.151G>C	p.Glu51Gln	missense_variant	Exon 2 of 16	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.61	N;N
PhyloP100		6.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.11
Sift	Benign	0.48	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0030	B;B
Vest4		0.18
MutPred		0.44		Loss of catalytic residue at E51 (P = 0.0986);Loss of catalytic residue at E51 (P = 0.0986);
MVP		0.35
MPC		0.13
ClinPred		0.46	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.37
Mutation Taster		=46/54	disease causing

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: rs2111964278; hg19: chr5-67522654;