chr10-94298541-C-T

Position:

chr10-94298541-C-T

Variant summary

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

The NM_016341.4(PLCE1):c.5330C>T(p.Thr1777Ile) variant causes a missense change. The variant allele was found at a frequency of 0.277 in 1,613,514 control chromosomes in the GnomAD database, including 64,048 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7705 hom., cov: 31)

Exomes 𝑓: 0.27 ( 56343 hom. )

Consequence

PLCE1
NM_016341.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.13

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 (HGNC:):

PLCE1 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=7.8240037E-4).

BP6

Variant 10-94298541-C-T is Benign according to our data. Variant chr10-94298541-C-T is described in ClinVar as [Benign]. Clinvar id is 260724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94298541-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 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.5330C>T	p.Thr1777Ile	missense_variant	24/33	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.5330C>T	p.Thr1777Ile	missense_variant	24/33	1	NM_016341.4	ENSP00000360431.2		Q9P212-1

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47289

AN:

151664

Hom.:

7685

Cov.:

show subpopulations

Gnomad AFR

AF:

0.412

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.251

Gnomad ASJ

AF:

0.441

Gnomad EAS

AF:

0.229

Gnomad SAS

AF:

0.260

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.331

GnomAD3 exomes

AF:

0.267

AC:

66545

AN:

249386

Hom.:

9712

AF XY:

0.271

AC XY:

36607

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.421

Gnomad AMR exome

AF:

0.164

Gnomad ASJ exome

AF:

0.423

Gnomad EAS exome

AF:

0.227

Gnomad SAS exome

AF:

0.262

Gnomad FIN exome

AF:

0.203

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.301

GnomAD4 exome

AF:

0.273

AC:

398957

AN:

1461732

Hom.:

56343

Cov.:

AF XY:

0.275

AC XY:

200008

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.426

Gnomad4 AMR exome

AF:

0.174

Gnomad4 ASJ exome

AF:

0.422

Gnomad4 EAS exome

AF:

0.235

Gnomad4 SAS exome

AF:

0.263

Gnomad4 FIN exome

AF:

0.206

Gnomad4 NFE exome

AF:

0.272

Gnomad4 OTH exome

AF:

0.297

GnomAD4 genome

AF:

0.312

AC:

47341

AN:

151782

Hom.:

7705

Cov.:

AF XY:

0.305

AC XY:

22649

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.413

Gnomad4 AMR

AF:

0.250

Gnomad4 ASJ

AF:

0.441

Gnomad4 EAS

AF:

0.228

Gnomad4 SAS

AF:

0.259

Gnomad4 FIN

AF:

0.192

Gnomad4 NFE

AF:

0.286

Gnomad4 OTH

AF:

0.330

Alfa

AF:

0.290

Hom.:

10441

Bravo

AF:

0.318

TwinsUK

AF:

0.276

AC:

1024

ALSPAC

AF:

0.257

AC:

991

ESP6500AA

AF:

0.394

AC:

1593

ESP6500EA

AF:

0.286

AC:

2378

ExAC

AF:

0.271

AC:

32743

Asia WGS

AF:

0.283

AC:

983

AN:

3478

EpiCase

AF:

0.304

EpiControl

AF:

0.306

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-Nilou Lab	Oct 25, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 25139097, 20729852) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 33% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 31. 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

0.033

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.29

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.50

T;T;.

MetaRNN

Benign

0.00078

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.5

N;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

3.8

N;N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.079

MPC

0.50

ClinPred

0.0052

GERP RS

5.6

Varity_R

0.069

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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