rs11548656

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.731A>G(p.His244Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0313 in 1,613,968 control chromosomes in the GnomAD database, including 939 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 76 hom., cov: 32)

Exomes 𝑓: 0.032 ( 863 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.10

Publications

23 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=0.0069028437).

BP6

Variant 16-81883307-A-G is Benign according to our data. Variant chr16-81883307-A-G is described in ClinVar as Benign. ClinVar VariationId is 472903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0263 (4002/152288) while in subpopulation NFE AF = 0.0377 (2564/68020). AF 95% confidence interval is 0.0365. There are 76 homozygotes in GnomAd4. There are 1960 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4002 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.731A>G	p.His244Arg	missense_variant	Exon 9 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.731A>G	p.His244Arg	missense_variant	Exon 10 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.731A>G	p.His244Arg	missense_variant	Exon 9 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.731A>G	p.His244Arg	missense_variant	Exon 10 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.731A>G	p.His244Arg	missense_variant	Exon 9 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.0263

AC:

4006

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00792

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0211

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0479

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0377

Gnomad OTH

AF:

0.0315

GnomAD2 exomes

AF:

0.0253

AC:

6323

AN:

249542

AF XY:

0.0253

show subpopulations

Gnomad AFR exome

AF:

0.00678

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.0284

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0460

Gnomad NFE exome

AF:

0.0357

Gnomad OTH exome

AF:

0.0328

GnomAD4 exome

AF:

0.0318

AC:

46439

AN:

1461680

Hom.:

863

Cov.:

AF XY:

0.0312

AC XY:

22658

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00669

AC:

224

AN:

33478

American (AMR)

AF:

0.0191

AC:

855

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0275

AC:

720

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00392

AC:

338

AN:

86256

European-Finnish (FIN)

AF:

0.0473

AC:

2524

AN:

53378

Middle Eastern (MID)

AF:

0.0241

AC:

139

AN:

5766

European-Non Finnish (NFE)

AF:

0.0359

AC:

39901

AN:

1111850

Other (OTH)

AF:

0.0288

AC:

1737

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2138

4277

6415

8554

10692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1430

2860

4290

5720

7150

<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:

0.0263

AC:

4002

AN:

152288

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

1960

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00789

AC:

328

AN:

41558

American (AMR)

AF:

0.0210

AC:

321

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00270

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0479

AC:

509

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0377

AC:

2564

AN:

68020

Other (OTH)

AF:

0.0307

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

203

407

610

814

1017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0306

Hom.:

Bravo

AF:

0.0245

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0384

AC:

148

ESP6500AA

AF:

0.00707

AC:

ESP6500EA

AF:

0.0349

AC:

296

ExAC

AF:

0.0253

AC:

3061

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0408

EpiControl

AF:

0.0404

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

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

Benign

0.19

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0069

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

PhyloP100

7.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.2

.;N

REVEL

Benign

0.068

Sift

Benign

0.62

.;T

Sift4G

Benign

0.60

T;T

Polyphen

0.062

B;.

Vest4

0.34

MPC

0.16

ClinPred

0.025

GERP RS

5.1

PromoterAI

0.035

Neutral

(source)

Varity_R

0.17

gMVP

0.56

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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