rs942676

Variant names:

• chr10-94316738-C-G
• rs942676
• NM_016341.4:c.6324C>G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_016341.4(PLCE1):​c.6324C>G​(p.Val2108Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,612,102 control chromosomes in the GnomAD database, including 22,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1569 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20484 hom.)
• Consequence: PLCE1 NM_016341.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.41

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]

NOC3L (HGNC:24034): (NOC3 like DNA replication regulator) Enables RNA binding activity. Predicted to be involved in DNA replication initiation. Predicted to act upstream of or within fat cell differentiation. Located in mitochondrion; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 10-94316738-C-G is Benign according to our data. Variant chr10-94316738-C-G is described in ClinVar as [Benign]. Clinvar id is 260729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-94316738-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCE1	NM_016341.4	c.6324C>G	p.Val2108Val	synonymous_variant	Exon 29 of 33	ENST00000371380.8	NP_057425.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCE1	ENST00000371380.8	c.6324C>G	p.Val2108Val	synonymous_variant	Exon 29 of 33	1	NM_016341.4	ENSP00000360431.2

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18804 AN: 152048 Hom.: 1570 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.146 AC: 36403 AN: 249302 Hom.: 3202 AF XY: 0.147 AC XY: 19920 AN XY: 135262

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.0767

Gnomad EAS exome AF: 0.000723

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.160 AC: 233965 AN: 1459936 Hom.: 20484 Cov.: 31 AF XY: 0.160 AC XY: 116043 AN XY: 726396

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0782

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.124 AC: 18801 AN: 152166 Hom.: 1569 Cov.: 32 AF XY: 0.125 AC XY: 9310 AN XY: 74360

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.0789

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.104

Alfa AF: 0.146 Hom.: 602

Bravo AF: 0.111

Asia WGS AF: 0.0610 AC: 213 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 37% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 34. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 3 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.6
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs942676; hg19: chr10-96076495;