rs2302976

Variant names:

• chr5-68273774-A-G
• rs2302976
• ENST00000517412.2:n.1319A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000517412.2(PIK3R1):​n.1319A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 662,194 control chromosomes in the GnomAD database, including 13,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3326 hom., cov: 32)
  • Exomes 𝑓: 0.20 (10359 hom.)
• Consequence: PIK3R1 ENST00000517412.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.93
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-68273774-A-G is Benign according to our data. Variant chr5-68273774-A-G is described in ClinVar as Benign. ClinVar VariationId is 1278596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIK3R1	NM_181523.3	c.428-165A>G		intron_variant	Intron 3 of 15	ENST00000521381.6	NP_852664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIK3R1	ENST00000521381.6	c.428-165A>G		intron_variant	Intron 3 of 15	1	NM_181523.3	ENSP00000428056.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31235 AN: 152050 Hom.: 3317 Cov.: 32

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.198 AC: 101148 AN: 510026 Hom.: 10359 Cov.: 6 AF XY: 0.199 AC XY: 53884 AN XY: 270480

African (AFR) AF: 0.221 AC: 3163 AN: 14298

American (AMR) AF: 0.119 AC: 3009 AN: 25222

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 3113 AN: 14570

East Asian (EAS) AF: 0.178 AC: 6172 AN: 34664

South Asian (SAS) AF: 0.214 AC: 9770 AN: 45548

European-Finnish (FIN) AF: 0.232 AC: 8559 AN: 36878

Middle Eastern (MID) AF: 0.159 AC: 325 AN: 2050

European-Non Finnish (NFE) AF: 0.199 AC: 61274 AN: 308660

Other (OTH) AF: 0.205 AC: 5763 AN: 28136

GnomAD4 genome AF: 0.206 AC: 31277 AN: 152168 Hom.: 3326 Cov.: 32 AF XY: 0.207 AC XY: 15380 AN XY: 74396

African (AFR) AF: 0.223 AC: 9258 AN: 41498

American (AMR) AF: 0.158 AC: 2420 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 768 AN: 3472

East Asian (EAS) AF: 0.176 AC: 913 AN: 5176

South Asian (SAS) AF: 0.223 AC: 1071 AN: 4810

European-Finnish (FIN) AF: 0.230 AC: 2436 AN: 10600

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13745 AN: 68006

Other (OTH) AF: 0.206 AC: 435 AN: 2114

Alfa AF: 0.201 Hom.: 12219

Bravo AF: 0.199

Asia WGS AF: 0.259 AC: 898 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Benign	0.75
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2302976; hg19: chr5-67569602; COSMIC: COSV57135936; COSMIC: COSV57135936;