19-18161380-A-T

Variant names:

• chr19-18161380-A-T
• rs2241088
• NM_005027.4:c.700A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005027.4(PIK3R2):​c.700A>T​(p.Ser234Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,091,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. S234R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10293162).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	NM_005027.4	MANE Select	c.700A>T	p.Ser234Cys	missense	Exon 6 of 16	NP_005018.2
	PIK3R2	NR_073517.2		n.1255A>T		non_coding_transcript_exon	Exon 6 of 16
	PIK3R2	NR_162071.1		n.1153+195A>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.700A>T	p.Ser234Cys	missense	Exon 6 of 16	ENSP00000222254.6
	ENSG00000268173	ENST00000593731.1	TSL:2	n.700A>T		non_coding_transcript_exon	Exon 6 of 25	ENSP00000471914.1
	PIK3R2	ENST00000617130.6	TSL:1	n.598+195A>T		intron	N/A	ENSP00000477864.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1091682 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 520454

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22032

American (AMR) AF: 0.00 AC: 0 AN: 9056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14084

East Asian (EAS) AF: 0.00 AC: 0 AN: 24152

South Asian (SAS) AF: 0.00 AC: 0 AN: 26970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2906

European-Non Finnish (NFE) AF: 0.00000216 AC: 2 AN: 926688

Other (OTH) AF: 0.00 AC: 0 AN: 43260

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.18	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.030
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0	B
Vest4		0.057
MutPred		0.43		Loss of phosphorylation at S234 (P = 0.0344)
MVP		0.10
MPC		0.66
ClinPred		0.51	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.27
Mutation Taster		=88/12	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: rs2241088; hg19: chr19-18272190;