NM_002661.5:c.82A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002661.5(PLCG2):c.82A>T(p.Met28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,614,186 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 16 hom., cov: 32)

Exomes 𝑓: 0.015 ( 218 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 8.94

Publications

26 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0093021095).

BP6

Variant 16-81786071-A-T is Benign according to our data. Variant chr16-81786071-A-T is described in ClinVar as Benign. ClinVar VariationId is 440153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.01 (1525/152338) while in subpopulation SAS AF = 0.017 (82/4826). AF 95% confidence interval is 0.015. There are 16 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1525 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.82A>T	p.Met28Leu	missense_variant	Exon 2 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.82A>T	p.Met28Leu	missense_variant	Exon 3 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.82A>T	p.Met28Leu	missense_variant	Exon 2 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.82A>T	p.Met28Leu	missense_variant	Exon 3 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.82A>T	p.Met28Leu	missense_variant	Exon 2 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1525

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0158

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.0108

AC:

2693

AN:

249582

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00426

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00635

Gnomad NFE exome

AF:

0.0146

Gnomad OTH exome

AF:

0.00825

GnomAD4 exome

AF:

0.0153

AC:

22358

AN:

1461848

Hom.:

218

Cov.:

AF XY:

0.0152

AC XY:

11080

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33480

American (AMR)

AF:

0.00436

AC:

195

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00253

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0207

AC:

1782

AN:

86258

European-Finnish (FIN)

AF:

0.00610

AC:

326

AN:

53420

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0172

AC:

19181

AN:

1111968

Other (OTH)

AF:

0.0112

AC:

676

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1128

2256

3384

4512

5640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

742

1484

2226

2968

3710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0100

AC:

1525

AN:

152338

Hom.:

Cov.:

AF XY:

0.00977

AC XY:

728

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00279

AC:

116

AN:

41588

American (AMR)

AF:

0.00981

AC:

150

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0170

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00772

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0158

AC:

1075

AN:

68028

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

156

233

311

389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00918

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00445

AC:

ESP6500EA

AF:

0.0132

AC:

110

ExAC

AF:

0.0111

AC:

1344

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0131

EpiControl

AF:

0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLCG2: BS1, BS2 -

Oct 26, 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial cold autoinflammatory syndrome 3

Benign:1

Feb 03, 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.26

T;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;D

MetaRNN

Benign

0.0093

T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

.;L;.

PhyloP100

8.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.82

N;.;N

REVEL

Benign

0.25

Sift

Benign

0.33

T;.;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.85

.;P;.

Vest4

0.38, 0.24

MutPred

0.53

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MPC

0.37

ClinPred

0.030

GERP RS

5.1

Varity_R

0.32

gMVP

0.66

Mutation Taster

=89/11

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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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