17-8828654-C-G

Position:

• chr17-8828654-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010855.4(PIK3R6):​c.1226G>C​(p.Gly409Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIK3R6 NM_001010855.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.265

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29346853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3R6	NM_001010855.4	c.1226G>C	p.Gly409Ala	missense_variant	11/20	ENST00000619866.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3R6	ENST00000619866.5	c.1226G>C	p.Gly409Ala	missense_variant	11/20	5	NM_001010855.4	P1
PIK3R6	ENST00000611951.4	c.*1291G>C		3_prime_UTR_variant, NMD_transcript_variant	11/20	2
PIK3R6	ENST00000613555.4	c.*1018G>C		3_prime_UTR_variant, NMD_transcript_variant	10/20	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.1226G>C (p.G409A) alteration is located in exon 11 (coding exon 10) of the PIK3R6 gene. This alteration results from a G to C substitution at nucleotide position 1226, causing the glycine (G) at amino acid position 409 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.0065	T;T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.80	T;.
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.29	T;T
PrimateAI	Uncertain	0.75	T
Sift4G	Benign	1.0	T;T
Polyphen		0.99	D;D
Vest4		0.44
MVP		0.22
GERP RS		3.3
Varity_R		0.051
gMVP		0.35

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-8731971;