10-94279840-G-C

Variant names:

• chr10-94279840-G-C
• rs2274224
• NM_016341.4:c.4724G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1575Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (16733 hom., cov: 32)
  • Exomes 𝑓: 0.44 (141765 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0810
• Publications: 68 publications found

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-AS1 (HGNC:45193): (PLCE1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 260720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016341.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	NM_016341.4	MANE Select	c.4724G>C	p.Arg1575Pro	missense	Exon 20 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.4676G>C	p.Arg1559Pro	missense	Exon 20 of 33	NP_001275918.1
	PLCE1	NM_001165979.2		c.3800G>C	p.Arg1267Pro	missense	Exon 19 of 32	NP_001159451.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.4724G>C	p.Arg1575Pro	missense	Exon 20 of 33	ENSP00000360431.2
	PLCE1	ENST00000371375.2	TSL:1	c.3800G>C	p.Arg1267Pro	missense	Exon 19 of 31	ENSP00000360426.1
	PLCE1	ENST00000692396.1		c.4676G>C	p.Arg1559Pro	missense	Exon 20 of 33	ENSP00000508605.1

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70706 AN: 151772 Hom.: 16716 Cov.: 32

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

GnomAD2 exomes AF: 0.436 AC: 108444 AN: 248886 AF XY: 0.437

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 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.: 33 AF XY: 0.439 AC XY: 319187 AN XY: 726410

African (AFR) AF: 0.561 AC: 18737 AN: 33420

American (AMR) AF: 0.349 AC: 15612 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 14081 AN: 26122

East Asian (EAS) AF: 0.499 AC: 19799 AN: 39668

South Asian (SAS) AF: 0.428 AC: 36883 AN: 86218

European-Finnish (FIN) AF: 0.344 AC: 18362 AN: 53384

Middle Eastern (MID) AF: 0.569 AC: 3274 AN: 5754

European-Non Finnish (NFE) AF: 0.437 AC: 485744 AN: 1110406

Other (OTH) AF: 0.459 AC: 27685 AN: 60320

GnomAD4 genome AF: 0.466 AC: 70758 AN: 151890 Hom.: 16733 Cov.: 32 AF XY: 0.461 AC XY: 34175 AN XY: 74192

African (AFR) AF: 0.549 AC: 22719 AN: 41394

American (AMR) AF: 0.396 AC: 6036 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1936 AN: 3470

East Asian (EAS) AF: 0.528 AC: 2727 AN: 5160

South Asian (SAS) AF: 0.433 AC: 2080 AN: 4804

European-Finnish (FIN) AF: 0.331 AC: 3485 AN: 10534

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30170 AN: 67966

Other (OTH) AF: 0.483 AC: 1020 AN: 2112

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

Submissions by phenotype

Nephrotic syndrome, type 3 Benign:4

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23688607, 29083407)

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Focal segmental glomerulosclerosis Benign:1

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.68
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.071	T
MetaRNN	Benign	0.000060	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.081
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.079
Sift	Benign	1.0	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.67
ClinPred		0.0018	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2274224; hg19: chr10-96039597; COSMIC: COSV53340523; COSMIC: COSV53340523;