NM_002661.5:c.784C>G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002661.5(PLCG2):c.784C>G(p.Leu262Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000275 in 1,600,272 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.07

Variant links:

Genes affected

PLCG2 (HGNC:9066): (phospholipase C gamma 2) The protein encoded by this gene is a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for transmitting signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene have been found in autoinflammation, antibody deficiency, and immune dysregulation syndrome and familial cold autoinflammatory syndrome 3. [provided by RefSeq, Mar 2014]

PLCG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.099505186).

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.784C>G	p.Leu262Val	missense_variant	Exon 10 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.784C>G	p.Leu262Val	missense_variant	Exon 11 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.784C>G	p.Leu262Val	missense_variant	Exon 10 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.784C>G	p.Leu262Val	missense_variant	Exon 11 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.784C>G	p.Leu262Val	missense_variant	Exon 10 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150470

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

240688

Hom.:

AF XY:

0.0000461

AC XY:

AN XY:

130166

show subpopulations

Gnomad AFR exome

AF:

0.0000683

Gnomad AMR exome

AF:

0.00

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:

0.0000733

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000290

AC:

AN:

1449802

Hom.:

Cov.:

AF XY:

0.0000347

AC XY:

AN XY:

720974

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

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:

0.0000372

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73274

show subpopulations

Gnomad4 AFR

AF:

0.0000245

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000662

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.784C>G (p.L262V) alteration is located in exon 10 (coding exon 9) of the PLCG2 gene. This alteration results from a C to G substitution at nucleotide position 784, causing the leucine (L) at amino acid position 262 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome 3;C3553961:Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Uncertain:1

May 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome 3

Uncertain:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 262 of the PLCG2 protein (p.Leu262Val). This variant is present in population databases (rs372563994, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PLCG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 540106). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.21

.;N

REVEL

Benign

0.061

Sift

Benign

0.32

.;T

Sift4G

Benign

0.35

T;T

Polyphen

0.23

B;.

Vest4

0.18

MVP

0.37

MPC

0.12

ClinPred

0.057

GERP RS

2.7

Varity_R

0.061

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over