rs2274223

chr10-94306584-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.06

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]

ACMG classification

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
PLCE1	NM_016341.4	c.5780A>G	p.His1927Arg	missense_variant	26/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8	c.5780A>G	p.His1927Arg	missense_variant	26/33	1	NM_016341.4	P1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47158 AN: 151938 Hom.: 7385 Cov.: 32

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

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

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

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

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:4

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

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 24116107, 25139097, 22203178, 20729852, 23826241, 22412849, 20729853, 24127316, 23688607) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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	0.045
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

Other links and lift over

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