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.1712A>G(p.Asn571Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,611,776 control chromosomes in the GnomAD database, including 73 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 65 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.36

Publications

21 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=0.0071565807).

BP6

Variant 16-81908570-A-G is Benign according to our data. Variant chr16-81908570-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00784 (1193/152226) while in subpopulation AMR AF = 0.0125 (192/15300). AF 95% confidence interval is 0.0111. There are 8 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1193 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002661.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCG2	NM_002661.5	MANE Select	c.1712A>G	p.Asn571Ser	missense	Exon 17 of 33	NP_002652.2
PLCG2	NM_001425749.1		c.1712A>G	p.Asn571Ser	missense	Exon 18 of 34	NP_001412678.1
PLCG2	NM_001425750.1		c.1712A>G	p.Asn571Ser	missense	Exon 17 of 33	NP_001412679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.1712A>G	p.Asn571Ser	missense	Exon 17 of 33	ENSP00000482457.1
PLCG2	ENST00000567980.5	TSL:1	n.1956A>G		non_coding_transcript_exon	Exon 16 of 20
PLCG2	ENST00000565054.7	TSL:5	c.1712A>G	p.Asn571Ser	missense	Exon 18 of 34	ENSP00000520638.1

Frequencies

GnomAD3 genomes

AF:

0.00786

AC:

1195

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00867

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0126

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.00759

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00675

AC:

1673

AN:

248008

AF XY:

0.00661

show subpopulations

Gnomad AFR exome

AF:

0.00829

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.00103

Gnomad NFE exome

AF:

0.00742

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.00646

AC:

9431

AN:

1459550

Hom.:

Cov.:

AF XY:

0.00640

AC XY:

4645

AN XY:

726074

show subpopulations

African (AFR)

AF:

0.00880

AC:

294

AN:

33422

American (AMR)

AF:

0.0128

AC:

572

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.0186

AC:

485

AN:

26058

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39664

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86032

European-Finnish (FIN)

AF:

0.000993

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.0312

AC:

143

AN:

4580

European-Non Finnish (NFE)

AF:

0.00643

AC:

7147

AN:

1111552

Other (OTH)

AF:

0.0103

AC:

619

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

460

920

1381

1841

2301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.00784

AC:

1193

AN:

152226

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

536

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00864

AC:

359

AN:

41538

American (AMR)

AF:

0.0125

AC:

192

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000623

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00757

AC:

515

AN:

68002

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

126

189

252

315

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:

0.00778

Hom.:

Bravo

AF:

0.00934

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00807

AC:

ESP6500EA

AF:

0.00765

AC:

ExAC

AF:

0.00626

AC:

758

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00966

EpiControl

AF:

0.00932

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Familial cold autoinflammatory syndrome 3 (1)

Familial cold autoinflammatory syndrome 3;C3553961:Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0072

MetaSVM

Uncertain

-0.0044

MutationAssessor

Benign

0.33

PhyloP100

2.4

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.35

REVEL

Uncertain

0.29

Sift

Uncertain

0.010

Sift4G

Uncertain

0.035

Polyphen

0.0010

Vest4

0.36

MVP

0.72

MPC

0.22

ClinPred

0.021

GERP RS

4.8

Varity_R

0.13

gMVP

0.36

Mutation Taster

=98/2

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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rs75472618

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over