17-8823413-T-G

Variant names:

• chr17-8823413-T-G
• rs374477477
• NM_001010855.4:c.1600A>C

Variant summary

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

The NM_001010855.4(PIK3R6):​c.1600A>C​(p.Ile534Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,437,232 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. 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. I534V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PIK3R6 NM_001010855.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19333687).

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.1600A>C	p.Ile534Leu	missense	Exon 14 of 20	NP_001010855.1	Q5UE93
	PIK3R6	NM_001290211.1		c.1192A>C	p.Ile398Leu	missense	Exon 14 of 20	NP_001277140.1	B3KRK9
	PIK3R6	NR_110865.1		n.1935A>C		non_coding_transcript_exon	Exon 13 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R6	ENST00000619866.5	TSL:5 MANE Select	c.1600A>C	p.Ile534Leu	missense	Exon 14 of 20	ENSP00000480157.1	Q5UE93
	PIK3R6	ENST00000907451.1		c.1600A>C	p.Ile534Leu	missense	Exon 14 of 20	ENSP00000577510.1
	PIK3R6	ENST00000907452.1		c.1585A>C	p.Ile529Leu	missense	Exon 14 of 20	ENSP00000577511.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248186 AF XY: 0.00000743

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: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1437232 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714926

African (AFR) AF: 0.00 AC: 0 AN: 32880

American (AMR) AF: 0.00 AC: 0 AN: 43674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25646

East Asian (EAS) AF: 0.00 AC: 0 AN: 38726

South Asian (SAS) AF: 0.00 AC: 0 AN: 82624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1096152

Other (OTH) AF: 0.00 AC: 0 AN: 59246

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000202 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T
PhyloP100		1.1
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.035	D
Polyphen		0.16	B
Vest4		0.47
MVP		0.095
GERP RS		-0.25
Varity_R		0.22
gMVP		0.50
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: rs374477477; hg19: chr17-8726730;