chr17-8827237-C-A

Variant names:

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

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>T​(p.Val484Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,443,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/13 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. V484I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIK3R6 NM_001010855.4 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.3691591).

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>T	p.Val484Leu	missense	Exon 13 of 20	NP_001010855.1	Q5UE93
	PIK3R6	NM_001290211.1		c.1042G>T	p.Val348Leu	missense	Exon 13 of 20	NP_001277140.1	B3KRK9
	PIK3R6	NR_110865.1		n.1785G>T		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>T	p.Val484Leu	missense	Exon 13 of 20	ENSP00000480157.1	Q5UE93
	PIK3R6	ENST00000907451.1		c.1450G>T	p.Val484Leu	missense	Exon 13 of 20	ENSP00000577510.1
	PIK3R6	ENST00000907452.1		c.1435G>T	p.Val479Leu	missense	Exon 13 of 20	ENSP00000577511.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000462 AC: 1 AN: 216314 AF XY: 0.00000859

Gnomad AFR exome AF: 0.00

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: 6.93e-7 AC: 1 AN: 1443488 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 716106

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

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

South Asian (SAS) AF: 0.0000121 AC: 1 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: 0.00 AC: 0 AN: 1103422

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.37	T
PhyloP100		4.1
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.095	T
Polyphen		0.39	B
Vest4		0.27
MVP		0.28
GERP RS		4.6
Varity_R		0.11
gMVP		0.37

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;