chr17-8827237-C-T

Variant names:

• chr17-8827237-C-T
• rs771187907
• NM_001010855.4:c.1450G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010855.4(PIK3R6):​c.1450G>A​(p.Val484Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000501 in 1,595,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PIK3R6 NM_001010855.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09
• Publications: 2 publications found

Genes affected

PIK3R6 (HGNC:27101): (phosphoinositide-3-kinase regulatory subunit 6) Phosphoinositide 3-kinase gamma is a lipid kinase that produces the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. The kinase is composed of a catalytic subunit and one of several regulatory subunits, and is chiefly activated by G protein-coupled receptors. This gene encodes a regulatory subunit, and is distantly related to the phosphoinositide-3-kinase, regulatory subunit 5 gene which is located adjacent to this gene on chromosome 7. The orthologous protein in the mouse binds to both the catalytic subunit and to G(beta/gamma), and mediates activation of the kinase subunit downstream of G protein-coupled receptors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37137368).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010855.4. 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
	PIK3R6	NM_001010855.4	MANE Select	c.1450G>A	p.Val484Ile	missense	Exon 13 of 20	NP_001010855.1	Q5UE93
	PIK3R6	NM_001290211.1		c.1042G>A	p.Val348Ile	missense	Exon 13 of 20	NP_001277140.1	B3KRK9
	PIK3R6	NR_110865.1		n.1785G>A		non_coding_transcript_exon	Exon 12 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R6	ENST00000619866.5	TSL:5 MANE Select	c.1450G>A	p.Val484Ile	missense	Exon 13 of 20	ENSP00000480157.1	Q5UE93
	PIK3R6	ENST00000907451.1		c.1450G>A	p.Val484Ile	missense	Exon 13 of 20	ENSP00000577510.1
	PIK3R6	ENST00000907452.1		c.1435G>A	p.Val479Ile	missense	Exon 13 of 20	ENSP00000577511.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.00000925 AC: 2 AN: 216314 AF XY: 0.00000859

Gnomad AFR exome AF: 0.000159

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1443488 Hom.: 0 Cov.: 30 AF XY: 0.00000559 AC XY: 4 AN XY: 716106

African (AFR) AF: 0.00 AC: 0 AN: 32966

American (AMR) AF: 0.00 AC: 0 AN: 42098

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 38680

South Asian (SAS) AF: 0.00 AC: 0 AN: 82932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1103422

Other (OTH) AF: 0.00 AC: 0 AN: 59772

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

African (AFR) AF: 0.0000724 AC: 3 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000357 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.00073	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.37	T
PhyloP100		4.1
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.13	T
Polyphen		0.74	P
Vest4		0.24
MVP		0.29
GERP RS		4.6
Varity_R		0.067
gMVP		0.20
Mutation Taster		=99/1	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: rs771187907; hg19: chr17-8730554; COSMIC: COSV100265985;