chr16-81912673-A-G

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.2011A>G(p.Ile671Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,612,688 control chromosomes in the GnomAD database, including 66 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I671I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 65 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.14

Publications

9 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=0.014680892).

BP6

Variant 16-81912673-A-G is Benign according to our data. Variant chr16-81912673-A-G is described in ClinVar as [Benign]. Clinvar id is 440160.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 = 0.00228 (347/152338) while in subpopulation SAS AF = 0.0228 (110/4820). AF 95% confidence interval is 0.0194. There are 1 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 347 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.2011A>G	p.Ile671Val	missense_variant	Exon 19 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.2011A>G	p.Ile671Val	missense_variant	Exon 20 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.2011A>G	p.Ile671Val	missense_variant	Exon 19 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.2011A>G	p.Ile671Val	missense_variant	Exon 20 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.2011A>G	p.Ile671Val	missense_variant	Exon 19 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.00228

AC:

347

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00163

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00545

AC:

1338

AN:

245280

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.000196

Gnomad AMR exome

AF:

0.00155

Gnomad ASJ exome

AF:

0.00912

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.000523

Gnomad NFE exome

AF:

0.00347

Gnomad OTH exome

AF:

0.00677

GnomAD4 exome

AF:

0.00361

AC:

5265

AN:

1460350

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

3107

AN XY:

726350

show subpopulations

African (AFR)

AF:

0.000658

AC:

AN:

33456

American (AMR)

AF:

0.00209

AC:

AN:

44534

Ashkenazi Jewish (ASJ)

AF:

0.00904

AC:

235

AN:

25998

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.0249

AC:

2139

AN:

85834

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.0210

AC:

121

AN:

5764

European-Non Finnish (NFE)

AF:

0.00207

AC:

2299

AN:

1111458

Other (OTH)

AF:

0.00489

AC:

295

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

258

517

775

1034

1292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00228

AC:

347

AN:

152338

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41588

American (AMR)

AF:

0.00163

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0228

AC:

110

AN:

4820

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00226

AC:

154

AN:

68020

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00339

Hom.:

Bravo

AF:

0.00194

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000735

AC:

ESP6500EA

AF:

0.00238

AC:

ExAC

AF:

0.00566

AC:

685

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 28, 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

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

-0.83

N;.

PhyloP100

3.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.39

.;N

REVEL

Uncertain

0.31

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.27

MVP

0.46

MPC

0.23

ClinPred

0.0068

GERP RS

4.0

Varity_R

0.094

gMVP

0.36

Mutation Taster

=94/6

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