17-8881007-G-T

Variant names:

• chr17-8881007-G-T
• rs772088859
• NM_001142633.3:c.2393C>A

Variant summary

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

The NM_001142633.3(PIK3R5):​c.2393C>A​(p.Ser798*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIK3R5 NM_001142633.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.85
• Publications: 0 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.2393C>A	p.Ser798*	stop_gained	Exon 18 of 19	NP_001136105.1	L7RT34
	PIK3R5	NM_014308.4		c.2393C>A	p.Ser798*	stop_gained	Exon 18 of 19	NP_055123.2	Q8WYR1-1
	PIK3R5	NM_001388396.1		c.2390C>A	p.Ser797*	stop_gained	Exon 18 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.2393C>A	p.Ser798*	stop_gained	Exon 18 of 19	ENSP00000392812.1	Q8WYR1-1
	PIK3R5	ENST00000581552.5	TSL:1	c.2393C>A	p.Ser798*	stop_gained	Exon 18 of 19	ENSP00000462433.1	Q8WYR1-1
	PIK3R5	ENST00000623421.3	TSL:1	c.1235C>A	p.Ser412*	stop_gained	Exon 17 of 18	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461336 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727044

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

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: 0.00000180 AC: 2 AN: 1111508

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.77	D
PhyloP100		4.8
Vest4		0.48
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs772088859; hg19: chr17-8784324;