NM_016341.4:c.2352C>T

Variant names:

• chr10-94236052-C-T
• rs201793869
• NM_016341.4:c.2352C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_016341.4(PLCE1):​c.2352C>T​(p.Asp784Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,990 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (42 hom.)
• Consequence: PLCE1 NM_016341.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.915
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 10-94236052-C-T is Benign according to our data. Variant chr10-94236052-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 301704.
• BP7: Synonymous conserved (PhyloP=0.915 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00124 (189/152224) while in subpopulation SAS AF = 0.0262 (126/4804). AF 95% confidence interval is 0.0225. There are 5 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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.2352C>T	p.Asp784Asp	synonymous	Exon 7 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.2352C>T	p.Asp784Asp	synonymous	Exon 7 of 33	NP_001275918.1	B7ZM61
	PLCE1	NM_001165979.2		c.1428C>T	p.Asp476Asp	synonymous	Exon 6 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.2352C>T	p.Asp784Asp	synonymous	Exon 7 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000371375.2	TSL:1	c.1428C>T	p.Asp476Asp	synonymous	Exon 6 of 31	ENSP00000360426.1	Q9P212-2
	PLCE1	ENST00000875452.1		c.2352C>T	p.Asp784Asp	synonymous	Exon 8 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152110 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00299 AC: 742 AN: 247994 AF XY: 0.00411

Gnomad AFR exome AF: 0.000844

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.00148 AC: 2159 AN: 1461766 Hom.: 42 Cov.: 31 AF XY: 0.00213 AC XY: 1548 AN XY: 727196

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39688

South Asian (SAS) AF: 0.0227 AC: 1957 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00381 AC: 22 AN: 5768

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111952

Other (OTH) AF: 0.00146 AC: 88 AN: 60396

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152224 Hom.: 5 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74418

African (AFR) AF: 0.000746 AC: 31 AN: 41544

American (AMR) AF: 0.00170 AC: 26 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0262 AC: 126 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Nephrotic syndrome, type 3 (2)
-	-	2	not provided (2)
-	1	-	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.46
PhyloP100		0.92
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: rs201793869; hg19: chr10-95995809;