17-8881806-G-C

Variant names:

• chr17-8881806-G-C
• rs201299435
• NM_001142633.3:c.2281C>G

Variant summary

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

The NM_001142633.3(PIK3R5):​c.2281C>G​(p.Arg761Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 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. R761W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIK3R5 NM_001142633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 2 publications found

Genes affected

PIK3R5 (HGNC:30035): (phosphoinositide-3-kinase regulatory subunit 5) Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory subunit of the class I PI3K gamma complex, which is a dimeric enzyme, consisting of a 110 kD catalytic subunit gamma and a regulatory subunit of either 55, 87 or 101 kD. This protein recruits the catalytic subunit from the cytosol to the plasma membrane through high-affinity interaction with G-beta-gamma proteins. Multiple alternatively spliced transcript variants encoding two distinct isoforms have been found. [provided by RefSeq, Oct 2011]

PIK3R5 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ataxia with oculomotor apraxia type 3

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LOC124903919 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142633.3. 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
	PIK3R5	NM_001142633.3	MANE Select	c.2281C>G	p.Arg761Gly	missense	Exon 16 of 19	NP_001136105.1	L7RT34
	PIK3R5	NM_014308.4		c.2281C>G	p.Arg761Gly	missense	Exon 16 of 19	NP_055123.2	Q8WYR1-1
	PIK3R5	NM_001388396.1		c.2278C>G	p.Arg760Gly	missense	Exon 16 of 19	NP_001375325.1	J3KSW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R5	ENST00000447110.6	TSL:5 MANE Select	c.2281C>G	p.Arg761Gly	missense	Exon 16 of 19	ENSP00000392812.1	Q8WYR1-1
	PIK3R5	ENST00000581552.5	TSL:1	c.2281C>G	p.Arg761Gly	missense	Exon 16 of 19	ENSP00000462433.1	Q8WYR1-1
	PIK3R5	ENST00000623421.3	TSL:1	c.1123C>G	p.Arg375Gly	missense	Exon 15 of 18	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251344 AF XY: 0.00000736

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: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.25
Sift	Benign	0.33	T
Sift4G	Uncertain	0.028	D
Polyphen		0.58	P
Vest4		0.46
MutPred		0.38		Loss of methylation at K758 (P = 0.0397)
MVP		0.29
MPC		0.73
ClinPred		0.42	T
GERP RS		1.1
PromoterAI		-0.13	Neutral
Varity_R		0.14
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201299435; hg19: chr17-8785123;