10-94324942-G-T

Variant names:

• chr10-94324942-G-T
• rs200113831
• NM_016341.4:c.6771G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016341.4(PLCE1):​c.6771G>T​(p.Lys2257Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K2257K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLCE1 NM_016341.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34356162).

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.6771G>T	p.Lys2257Asn	missense	Exon 32 of 33	NP_057425.3
	PLCE1	NM_001288989.2		c.6723G>T	p.Lys2241Asn	missense	Exon 32 of 33	NP_001275918.1	B7ZM61
	PLCE1	NM_001165979.2		c.5847G>T	p.Lys1949Asn	missense	Exon 31 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.6771G>T	p.Lys2257Asn	missense	Exon 32 of 33	ENSP00000360431.2	Q9P212-1
	PLCE1	ENST00000371375.2	TSL:1	c.5847G>T	p.Lys1949Asn	missense	Exon 31 of 31	ENSP00000360426.1	Q9P212-2
	PLCE1	ENST00000875452.1		c.6771G>T	p.Lys2257Asn	missense	Exon 33 of 34	ENSP00000545511.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.15		Loss of methylation at K2257 (P = 0.0099)
MVP		0.67
MPC		1.4
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.49
gMVP		0.39
Mutation Taster		=63/37	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: rs200113831; hg19: chr10-96084699;