rs61732521

chr10-94246311-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP2 BP4_Strong BP6 BS1

The NM_016341.4(PLCE1):c.2786G>C(p.Ser929Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.00069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.67

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PLCE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.011840969).
• BP6: Variant 10-94246311-G-C is Benign according to our data. Variant chr10-94246311-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586319.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000689 (105/152334) while in subpopulation AFR AF= 0.00243 (101/41566). AF 95% confidence interval is 0.00205. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCE1	NM_016341.4	c.2786G>C	p.Ser929Thr	missense_variant	8/33	ENST00000371380.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCE1	ENST00000371380.8	c.2786G>C	p.Ser929Thr	missense_variant	8/33	1	NM_016341.4	P1

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000177 AC: 44 AN: 249268 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135288

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000670 AC: 98 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34 AN XY: 727242

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74504

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000595 Hom.: 0

Bravo AF: 0.000956

ESP6500AA AF: 0.00236 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000199 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jun 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	19
Dann	Benign	0.83
DEOGEN2	Benign	0.060	T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.29	N;N;N
REVEL	Benign	0.062
Sift	Benign	0.24	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0090	B;B;B
Vest4		0.29
MVP		0.56
MPC		0.086
ClinPred		0.033	T
GERP RS		2.7
Varity_R		0.053
gMVP		0.21

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: rs61732521; hg19: chr10-96006068;