Genetic Variant NM_005027.4:c.2093A>T (chr19-18169200-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_005027.4(PIK3R2):c.2093A>T(p.His698Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H698P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PIK3R2
NM_005027.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.29

Publications

0 publications found

Variant links:

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

PIK3R2 links:

ENSG00000268173 (HGNC:):

ENSG00000268173 links:

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ACMG classification

Classification was made for transcript

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_005027.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIK3R2	NM_005027.4	MANE Select	c.2093A>T	p.His698Leu	missense	Exon 16 of 16	NP_005018.2
PIK3R2	NR_073517.2		n.2697A>T		non_coding_transcript_exon	Exon 16 of 16
PIK3R2	NR_162071.1		n.2435A>T		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIK3R2	ENST00000222254.13	TSL:1 MANE Select	c.2093A>T	p.His698Leu	missense	Exon 16 of 16	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1	TSL:2	n.2093A>T		non_coding_transcript_exon	Exon 16 of 25	ENSP00000471914.1
PIK3R2	ENST00000617130.6	TSL:1	n.*1121A>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000477864.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

PhyloP100

7.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.28

Sift

Benign

0.12

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.47

MutPred

0.46

Loss of disorder (P = 0.1284)

MVP

0.54

MPC

1.1

ClinPred

0.97

GERP RS

3.0

Varity_R

0.48

gMVP

0.42

Mutation Taster

=57/43

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over