rs140727165

Variant names:

• chr17-8881651-T-C
• rs140727165
• NM_001142633.3:c.2361A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001142633.3(PIK3R5):​c.2361A>G​(p.Lys787Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,394 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: PIK3R5 NM_001142633.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.334
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 17-8881651-T-C is Benign according to our data. Variant chr17-8881651-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3047480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.334 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.2361A>G	p.Lys787Lys	synonymous	Exon 17 of 19	NP_001136105.1	L7RT34
	PIK3R5	NM_014308.4		c.2361A>G	p.Lys787Lys	synonymous	Exon 17 of 19	NP_055123.2	Q8WYR1-1
	PIK3R5	NM_001388396.1		c.2358A>G	p.Lys786Lys	synonymous	Exon 17 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.2361A>G	p.Lys787Lys	synonymous	Exon 17 of 19	ENSP00000392812.1	Q8WYR1-1
	PIK3R5	ENST00000581552.5	TSL:1	c.2361A>G	p.Lys787Lys	synonymous	Exon 17 of 19	ENSP00000462433.1	Q8WYR1-1
	PIK3R5	ENST00000623421.3	TSL:1	c.1203A>G	p.Lys401Lys	synonymous	Exon 16 of 18	ENSP00000485280.1	Q8WYR1-2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000329 AC: 82 AN: 249536 AF XY: 0.000200

Gnomad AFR exome AF: 0.00379

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461110 Hom.: 2 Cov.: 32 AF XY: 0.0000826 AC XY: 60 AN XY: 726760

African (AFR) AF: 0.00320 AC: 107 AN: 33472

American (AMR) AF: 0.000493 AC: 22 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111604

Other (OTH) AF: 0.000348 AC: 21 AN: 60364

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74474

African (AFR) AF: 0.00344 AC: 143 AN: 41556

American (AMR) AF: 0.000719 AC: 11 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000575 Hom.: 0

Bravo AF: 0.000986

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PIK3R5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.1
DANN	Benign	0.66
PhyloP100		0.33
PromoterAI		0.0011	Neutral
Mutation Taster		=100/0	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: rs140727165; hg19: chr17-8784968;