16-81889208-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002661.5(PLCG2):c.802C>T(p.Arg268Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,602,822 control chromosomes in the GnomAD database, including 3,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.046 ( 210 hom., cov: 31)

Exomes 𝑓: 0.058 ( 2872 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.789

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 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=0.0027187467).

BP6

Variant 16-81889208-C-T is Benign according to our data. Variant chr16-81889208-C-T is described in ClinVar as [Benign]. Clinvar id is 403319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81889208-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5 link	c.802C>T	p.Arg268Trp	missense_variant	Exon 10 of 33	ENST00000564138.6	NP_002652.2	P16885
PLCG2	NM_001425749.1 link	c.802C>T	p.Arg268Trp	missense_variant	Exon 11 of 34		NP_001412678.1
PLCG2	NM_001425750.1 link	c.802C>T	p.Arg268Trp	missense_variant	Exon 10 of 33		NP_001412679.1
PLCG2	NM_001425751.1 link	c.802C>T	p.Arg268Trp	missense_variant	Exon 11 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6 link	c.802C>T	p.Arg268Trp	missense_variant	Exon 10 of 33	1	NM_002661.5	ENSP00000482457.1		P16885

Frequencies

GnomAD3 genomes

AF:

0.0458

AC:

6836

AN:

149408

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0444

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0171

Gnomad FIN

AF:

0.0487

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0682

Gnomad OTH

AF:

0.0515

GnomAD2 exomes

AF:

0.0465

AC:

11244

AN:

242006

AF XY:

0.0470

show subpopulations

Gnomad AFR exome

AF:

0.00950

Gnomad AMR exome

AF:

0.0327

Gnomad ASJ exome

AF:

0.101

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.0502

Gnomad NFE exome

AF:

0.0652

Gnomad OTH exome

AF:

0.0544

GnomAD4 exome

AF:

0.0581

AC:

84487

AN:

1453296

Hom.:

2872

Cov.:

AF XY:

0.0576

AC XY:

41625

AN XY:

722636

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

AC:

337

AN:

33400

Gnomad4 AMR exome

AF:

0.0351

AC:

1554

AN:

44240

Gnomad4 ASJ exome

AF:

0.104

AC:

2704

AN:

25906

Gnomad4 EAS exome

AF:

0.000126

AC:

AN:

39658

Gnomad4 SAS exome

AF:

0.0159

AC:

1350

AN:

84918

Gnomad4 FIN exome

AF:

0.0511

AC:

2719

AN:

53166

Gnomad4 NFE exome

AF:

0.0652

AC:

72101

AN:

1106136

Gnomad4 Remaining exome

AF:

0.0566

AC:

3404

AN:

60124

Heterozygous variant carriers

3259

6518

9778

13037

16296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

2554

5108

7662

10216

12770

<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:

0.0457

AC:

6834

AN:

149526

Hom.:

210

Cov.:

AF XY:

0.0441

AC XY:

3210

AN XY:

72788

show subpopulations

Gnomad4 AFR

AF:

0.0111

AC:

0.0110887

AN:

0.0110887

Gnomad4 AMR

AF:

0.0444

AC:

0.0443707

AN:

0.0443707

Gnomad4 ASJ

AF:

0.103

AC:

0.103239

AN:

0.103239

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.0172

AC:

0.0171635

AN:

0.0171635

Gnomad4 FIN

AF:

0.0487

AC:

0.048721

AN:

0.048721

Gnomad4 NFE

AF:

0.0682

AC:

0.0682403

AN:

0.0682403

Gnomad4 OTH

AF:

0.0510

AC:

0.0509709

AN:

0.0509709

Heterozygous variant carriers

281

562

844

1125

1406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0616

Hom.:

1406

Bravo

AF:

0.0454

TwinsUK

AF:

0.0696

AC:

258

ALSPAC

AF:

0.0618

AC:

238

ESP6500AA

AF:

0.0115

AC:

ESP6500EA

AF:

0.0694

AC:

580

ExAC

AF:

0.0445

AC:

5386

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

0.20

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.46

PROVEAN

Benign

0.98

.;N

REVEL

Benign

0.15

Sift

Benign

0.030

.;D

Sift4G

Uncertain

0.041

D;D

Polyphen

0.99

D;.

Vest4

0.39

MPC

0.34

ClinPred

0.025

GERP RS

2.8

Varity_R

0.15

gMVP

0.72

Mutation Taster

=84/16

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over