rs187956469

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002661.5(PLCG2):c.1444T>C(p.Tyr482His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,613,982 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y482Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 24 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.09

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
familial cold autoinflammatory syndrome 3
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

PLCG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008223802).

BP6

Variant 16-81905484-T-C is Benign according to our data. Variant chr16-81905484-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440158.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152326) while in subpopulation NFE AF = 0.00509 (346/68014). AF 95% confidence interval is 0.00465. There are 1 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 512 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.1444T>C	p.Tyr482His	missense_variant	Exon 15 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.1444T>C	p.Tyr482His	missense_variant	Exon 16 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.1444T>C	p.Tyr482His	missense_variant	Exon 15 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.1444T>C	p.Tyr482His	missense_variant	Exon 16 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.1444T>C	p.Tyr482His	missense_variant	Exon 15 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

512

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00509

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00360

AC:

898

AN:

249386

AF XY:

0.00355

show subpopulations

Gnomad AFR exome

AF:

0.000841

Gnomad AMR exome

AF:

0.00386

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000974

Gnomad NFE exome

AF:

0.00476

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00392

AC:

5737

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

2824

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33478

American (AMR)

AF:

0.00380

AC:

170

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0146

AC:

381

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00107

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00125

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00420

AC:

4669

AN:

1111806

Other (OTH)

AF:

0.00489

AC:

295

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

268

537

805

1074

1342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00336

AC:

512

AN:

152326

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

221

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41580

American (AMR)

AF:

0.00392

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00509

AC:

346

AN:

68014

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.00362

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000488

AC:

ESP6500EA

AF:

0.00489

AC:

ExAC

AF:

0.00330

AC:

399

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00643

EpiControl

AF:

0.00504

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLCG2: BS2 -

Sep 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome 3

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;.

Eigen

Benign

0.00052

Eigen_PC

Benign

0.0084

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

3.1

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.5

.;D

REVEL

Benign

0.13

Sift

Benign

0.056

.;T

Sift4G

Uncertain

0.059

T;T

Polyphen

0.97

D;.

Vest4

0.17

MVP

0.71

MPC

0.35

ClinPred

0.024

GERP RS

2.9

Varity_R

0.18

gMVP

0.49

Mutation Taster

=88/12

polymorphism

(source)

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

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rs187956469

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over