19-18167318-C-T

Variant names:

• chr19-18167318-C-T
• rs112411913
• NM_005027.4:c.1736+12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005027.4(PIK3R2):​c.1736+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,557,014 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (17 hom., cov: 31)
  • Exomes 𝑓: 0.00078 (14 hom.)
• Consequence: PIK3R2 NM_005027.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.24
• Publications: 0 publications found

Genes affected

PIK3R2 (HGNC:8980): (phosphoinositide-3-kinase regulatory subunit 2) Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

PIK3R2 Gene-Disease associations (from GenCC):

• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Genomics England PanelApp
• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000268173 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-18167318-C-T is Benign according to our data. Variant chr19-18167318-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0071 (1081/152306) while in subpopulation AFR AF = 0.024 (998/41560). AF 95% confidence interval is 0.0228. There are 17 homozygotes in GnomAd4. There are 535 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1081 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005027.4. 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
	PIK3R2	NM_005027.4	MANE Select	c.1736+12C>T		intron	N/A	NP_005018.2
	PIK3R2	NR_073517.2		n.2340+12C>T		intron	N/A
	PIK3R2	NR_162071.1		n.2074+12C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.1736+12C>T		intron	N/A	ENSP00000222254.6
	ENSG00000268173	ENST00000593731.1	TSL:2	n.1736+12C>T		intron	N/A	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.*764+12C>T		intron	N/A	ENSP00000477864.2

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1069 AN: 152188 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00206 AC: 433 AN: 209800 AF XY: 0.00161

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.000128

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000613

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000776 AC: 1090 AN: 1404708 Hom.: 14 Cov.: 30 AF XY: 0.000701 AC XY: 487 AN XY: 694796

African (AFR) AF: 0.0266 AC: 816 AN: 30682

American (AMR) AF: 0.00252 AC: 94 AN: 37342

Ashkenazi Jewish (ASJ) AF: 0.0000415 AC: 1 AN: 24082

East Asian (EAS) AF: 0.00 AC: 0 AN: 36028

South Asian (SAS) AF: 0.0000629 AC: 5 AN: 79466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52532

Middle Eastern (MID) AF: 0.00125 AC: 7 AN: 5604

European-Non Finnish (NFE) AF: 0.0000194 AC: 21 AN: 1081090

Other (OTH) AF: 0.00252 AC: 146 AN: 57882

GnomAD4 genome AF: 0.00710 AC: 1081 AN: 152306 Hom.: 17 Cov.: 31 AF XY: 0.00718 AC XY: 535 AN XY: 74478

African (AFR) AF: 0.0240 AC: 998 AN: 41560

American (AMR) AF: 0.00426 AC: 65 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00609 Hom.: 1

Bravo AF: 0.00826

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.6
DANN	Benign	0.51
PhyloP100		1.2
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: rs112411913; hg19: chr19-18278128;