chr10-94031273-C-T

Variant names:

• chr10-94031273-C-T
• rs61749238
• NM_016341.4:c.227C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016341.4(PLCE1):​c.227C>T​(p.Ala76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,613,686 control chromosomes in the GnomAD database, including 4 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A76E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.26
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055702627).
• BP6: Variant 10-94031273-C-T is Benign according to our data. Variant chr10-94031273-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00317 (483/152156) while in subpopulation AFR AF = 0.0111 (461/41514). AF 95% confidence interval is 0.0103. There are 2 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.227C>T	p.Ala76Val	missense	Exon 2 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.227C>T	p.Ala76Val	missense	Exon 2 of 33	NP_001275918.1	B7ZM61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCE1	ENST00000371380.8	TSL:1 MANE Select	c.227C>T	p.Ala76Val	missense	Exon 2 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000875452.1		c.227C>T	p.Ala76Val	missense	Exon 3 of 34	ENSP00000545511.1
	PLCE1	ENST00000875451.1		c.227C>T	p.Ala76Val	missense	Exon 2 of 33	ENSP00000545510.1

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 484 AN: 152038 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

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: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000867 AC: 215 AN: 247942 AF XY: 0.000758

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000313 AC: 457 AN: 1461530 Hom.: 2 Cov.: 33 AF XY: 0.000270 AC XY: 196 AN XY: 727054

African (AFR) AF: 0.0109 AC: 364 AN: 33464

American (AMR) AF: 0.000850 AC: 38 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53336

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

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111840

Other (OTH) AF: 0.000547 AC: 33 AN: 60380

GnomAD4 genome AF: 0.00317 AC: 483 AN: 152156 Hom.: 2 Cov.: 32 AF XY: 0.00311 AC XY: 231 AN XY: 74372

African (AFR) AF: 0.0111 AC: 461 AN: 41514

American (AMR) AF: 0.000852 AC: 13 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67998

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

Alfa AF: 0.00126 Hom.: 2

Bravo AF: 0.00369

ESP6500AA AF: 0.0121 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00100 AC: 121

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Nephrotic syndrome, type 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.084
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		0.010	B
Vest4		0.074
MVP		0.75
MPC		0.12
ClinPred		0.041	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.33
Mutation Taster		=92/8	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: rs61749238; hg19: chr10-95791030;