rs1143687

Positions:

chr16-81889208-C-T

Variant summary

Our verdict is Benign. Variant got -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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
PLCG2	NM_002661.5 linkuse as main transcript	c.802C>T	p.Arg268Trp	missense_variant	10/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6 linkuse as main transcript	c.802C>T	p.Arg268Trp	missense_variant	10/33	1	NM_002661.5	P1

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

GnomAD3 exomes

AF:

0.0465

AC:

11244

AN:

242006

Hom.:

337

AF XY:

0.0470

AC XY:

6157

AN XY:

130952

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 SAS exome

AF:

0.0160

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

Gnomad4 AMR exome

AF:

0.0351

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0159

Gnomad4 FIN exome

AF:

0.0511

Gnomad4 NFE exome

AF:

0.0652

Gnomad4 OTH exome

AF:

0.0566

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

Gnomad4 AMR

AF:

0.0444

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.0487

Gnomad4 NFE

AF:

0.0682

Gnomad4 OTH

AF:

0.0510

Alfa

AF:

0.0660

Hom.:

709

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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;.

MutationTaster

Benign

1.0

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

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