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rs2274223

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_016341.4(PLCE1):c.5780A>G(p.His1927Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,613,668 control chromosomes in the GnomAD database, including 74,193 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7401 hom., cov: 32)
Exomes 𝑓: 0.30 ( 66792 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.06
Variant links:
Genes affected
PLCE1 (HGNC:17175): (phospholipase C epsilon 1) This gene encodes a phospholipase enzyme that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These second messengers subsequently regulate various processes affecting cell growth, differentiation, and gene expression. This enzyme is regulated by small monomeric GTPases of the Ras and Rho families and by heterotrimeric G proteins. In addition to its phospholipase C catalytic activity, this enzyme has an N-terminal domain with guanine nucleotide exchange (GEF) activity. Mutations in this gene cause early-onset nephrotic syndrome; characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Sep 2009]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant where missense usually causes diseases, PLCE1
BP4
Computational evidence support a benign effect (MetaRNN=0.004501492).
BP6
Variant 10-94306584-A-G is Benign according to our data. Variant chr10-94306584-A-G is described in ClinVar as [Benign]. Clinvar id is 260728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94306584-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLCE1NM_016341.4 linkuse as main transcriptc.5780A>G p.His1927Arg missense_variant 26/33 ENST00000371380.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLCE1ENST00000371380.8 linkuse as main transcriptc.5780A>G p.His1927Arg missense_variant 26/331 NM_016341.4 P1Q9P212-1

Frequencies

GnomAD3 genomes
AF:
0.310
AC:
47158
AN:
151938
Hom.:
7385
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.346
Gnomad AMI
AF:
0.339
Gnomad AMR
AF:
0.253
Gnomad ASJ
AF:
0.450
Gnomad EAS
AF:
0.229
Gnomad SAS
AF:
0.283
Gnomad FIN
AF:
0.210
Gnomad MID
AF:
0.472
Gnomad NFE
AF:
0.317
Gnomad OTH
AF:
0.330
GnomAD3 exomes
AF:
0.282
AC:
70230
AN:
249328
Hom.:
10567
AF XY:
0.287
AC XY:
38888
AN XY:
135272
show subpopulations
Gnomad AFR exome
AF:
0.350
Gnomad AMR exome
AF:
0.169
Gnomad ASJ exome
AF:
0.437
Gnomad EAS exome
AF:
0.229
Gnomad SAS exome
AF:
0.283
Gnomad FIN exome
AF:
0.222
Gnomad NFE exome
AF:
0.310
Gnomad OTH exome
AF:
0.318
GnomAD4 exome
AF:
0.299
AC:
436911
AN:
1461612
Hom.:
66792
Cov.:
36
AF XY:
0.301
AC XY:
218919
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.354
Gnomad4 AMR exome
AF:
0.179
Gnomad4 ASJ exome
AF:
0.434
Gnomad4 EAS exome
AF:
0.236
Gnomad4 SAS exome
AF:
0.283
Gnomad4 FIN exome
AF:
0.226
Gnomad4 NFE exome
AF:
0.304
Gnomad4 OTH exome
AF:
0.315
GnomAD4 genome
AF:
0.310
AC:
47199
AN:
152056
Hom.:
7401
Cov.:
32
AF XY:
0.304
AC XY:
22575
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.346
Gnomad4 AMR
AF:
0.252
Gnomad4 ASJ
AF:
0.450
Gnomad4 EAS
AF:
0.229
Gnomad4 SAS
AF:
0.281
Gnomad4 FIN
AF:
0.210
Gnomad4 NFE
AF:
0.317
Gnomad4 OTH
AF:
0.328
Alfa
AF:
0.322
Hom.:
17558
Bravo
AF:
0.313
TwinsUK
AF:
0.309
AC:
1147
ALSPAC
AF:
0.293
AC:
1130
ESP6500AA
AF:
0.334
AC:
1345
ESP6500EA
AF:
0.311
AC:
2596
ExAC
AF:
0.284
AC:
34369
Asia WGS
AF:
0.289
AC:
1003
AN:
3478
EpiCase
AF:
0.332
EpiControl
AF:
0.332

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:4
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 09, 2014- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabOct 25, 2021- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not specified Benign:2
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 12, 2018This variant is associated with the following publications: (PMID: 24116107, 25139097, 22203178, 20729852, 23826241, 22412849, 20729853, 24127316, 23688607) -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Focal segmental glomerulosclerosis Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 27, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.045
BayesDel_addAF
Benign
-0.63
T
BayesDel_noAF
Benign
-0.53
Cadd
Benign
19
Dann
Benign
0.43
DEOGEN2
Benign
0.12
T;.;.
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.46
N
LIST_S2
Benign
0.18
T;T;.
MetaRNN
Benign
0.0045
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.95
N;.;.
MutationTaster
Benign
1.0
P;P;P;P
PrimateAI
Benign
0.43
T
PROVEAN
Benign
2.6
N;N;N
REVEL
Benign
0.15
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;B;B
Vest4
0.046
MPC
0.57
ClinPred
0.0027
T
GERP RS
5.4
Varity_R
0.068
gMVP
0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2274223; hg19: chr10-96066341; COSMIC: COSV53339364; API