rs202171627

Variant names:

• chr10-94306586-G-A
• rs202171627
• NM_016341.4:c.5782G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_016341.4(PLCE1):​c.5782G>A​(p.Val1928Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00019 in 1,614,010 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.14
• Publications: 0 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 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062835217).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000985 (150/152284) while in subpopulation AFR AF = 0.00318 (132/41560). AF 95% confidence interval is 0.00274. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	NM_016341.4	MANE Select	c.5782G>A	p.Val1928Ile	missense	Exon 26 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.5734G>A	p.Val1912Ile	missense	Exon 26 of 33	NP_001275918.1	B7ZM61
	PLCE1	NM_001165979.2		c.4858G>A	p.Val1620Ile	missense	Exon 25 of 32	NP_001159451.1	Q9P212-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.5782G>A	p.Val1928Ile	missense	Exon 26 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000371375.2	TSL:1	c.4858G>A	p.Val1620Ile	missense	Exon 25 of 31	ENSP00000360426.1	Q9P212-2
	PLCE1	ENST00000875452.1		c.5782G>A	p.Val1928Ile	missense	Exon 27 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000253 AC: 63 AN: 249302 AF XY: 0.000200

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461726 Hom.: 1 Cov.: 33 AF XY: 0.0000853 AC XY: 62 AN XY: 727184

African (AFR) AF: 0.00382 AC: 128 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111860

Other (OTH) AF: 0.000215 AC: 13 AN: 60392

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74454

African (AFR) AF: 0.00318 AC: 132 AN: 41560

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000331 Hom.: 0

Bravo AF: 0.00113

ESP6500AA AF: 0.00348 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000256 AC: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	-	Nephrotic syndrome, type 3 (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	PLCE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.51	N
PhyloP100		4.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.10
Sift	Benign	0.52	T
Sift4G	Benign	0.21	T
Polyphen		0.45	B
Vest4		0.10
MVP		0.69
MPC		0.73
ClinPred		0.066	T
GERP RS		4.5
Varity_R		0.067
gMVP		0.086
Mutation Taster		=100/0	polymorphism

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: rs202171627; hg19: chr10-96066343; COSMIC: COSV53375276;