10-94279840-G-C

Position:

chr10-94279840-G-C

Variant summary

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

The NM_016341.4(PLCE1):c.4724G>C(p.Arg1575Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,611,868 control chromosomes in the GnomAD database, including 158,498 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 16733 hom., cov: 32)

Exomes 𝑓: 0.44 ( 141765 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0810

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]

PLCE1 links:

PLCE1-AS1 (HGNC:):

PLCE1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCE1. . Gene score misZ 1.381 (greater than the threshold 3.09). Trascript score misZ 3.1046 (greater than threshold 3.09). GenCC has associacion of gene with nephrotic syndrome, type 3, familial idiopathic steroid-resistant nephrotic syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=5.9511298E-5).

BP6

Variant 10-94279840-G-C is Benign according to our data. Variant chr10-94279840-G-C is described in ClinVar as [Benign]. Clinvar id is 260720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94279840-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCE1	NM_016341.4 linkuse as main transcript	c.4724G>C	p.Arg1575Pro	missense_variant	20/33	ENST00000371380.8	NP_057425.3	Q9P212-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8 linkuse as main transcript	c.4724G>C	p.Arg1575Pro	missense_variant	20/33	1	NM_016341.4	ENSP00000360431.2		Q9P212-1

Frequencies

GnomAD3 genomes

AF:

0.466

AC:

70706

AN:

151772

Hom.:

16716

Cov.:

show subpopulations

Gnomad AFR

AF:

0.549

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.397

Gnomad ASJ

AF:

0.558

Gnomad EAS

AF:

0.529

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.444

Gnomad OTH

AF:

0.486

GnomAD3 exomes

AF:

0.436

AC:

108444

AN:

248886

Hom.:

24218

AF XY:

0.437

AC XY:

59031

AN XY:

135000

show subpopulations

Gnomad AFR exome

AF:

0.556

Gnomad AMR exome

AF:

0.344

Gnomad ASJ exome

AF:

0.538

Gnomad EAS exome

AF:

0.546

Gnomad SAS exome

AF:

0.427

Gnomad FIN exome

AF:

0.345

Gnomad NFE exome

AF:

0.439

Gnomad OTH exome

AF:

0.465

GnomAD4 exome

AF:

0.438

AC:

640177

AN:

1459978

Hom.:

141765

Cov.:

AF XY:

0.439

AC XY:

319187

AN XY:

726410

show subpopulations

Gnomad4 AFR exome

AF:

0.561

Gnomad4 AMR exome

AF:

0.349

Gnomad4 ASJ exome

AF:

0.539

Gnomad4 EAS exome

AF:

0.499

Gnomad4 SAS exome

AF:

0.428

Gnomad4 FIN exome

AF:

0.344

Gnomad4 NFE exome

AF:

0.437

Gnomad4 OTH exome

AF:

0.459

GnomAD4 genome

AF:

0.466

AC:

70758

AN:

151890

Hom.:

16733

Cov.:

AF XY:

0.461

AC XY:

34175

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.549

Gnomad4 AMR

AF:

0.396

Gnomad4 ASJ

AF:

0.558

Gnomad4 EAS

AF:

0.528

Gnomad4 SAS

AF:

0.433

Gnomad4 FIN

AF:

0.331

Gnomad4 NFE

AF:

0.444

Gnomad4 OTH

AF:

0.483

Alfa

AF:

0.393

Hom.:

1896

Bravo

AF:

0.475

TwinsUK

AF:

0.442

AC:

1639

ALSPAC

AF:

0.428

AC:

1650

ESP6500AA

AF:

0.545

AC:

2066

ESP6500EA

AF:

0.444

AC:

3651

ExAC

AF:

0.437

AC:

52817

Asia WGS

AF:

0.480

AC:

1670

AN:

3478

EpiCase

AF:

0.453

EpiControl

AF:

0.458

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 3

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 23688607, 29083407) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 54% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 50. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.053

T;.;.

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.071

T;T;.

MetaRNN

Benign

0.000060

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.55

N;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

1.6

N;N;N

REVEL

Benign

0.079

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.054

MPC

0.67

ClinPred

0.0018

GERP RS

4.6

Varity_R

0.12

gMVP

0.18

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over