rs72824905

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002661.5(PLCG2):c.1565C>G(p.Pro522Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,613,548 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P522L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0049 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0069 ( 43 hom. )

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.56

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=0.0038388371).

BP6

Variant 16-81908423-C-G is Benign according to our data. Variant chr16-81908423-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 440154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81908423-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00494 (752/152236) while in subpopulation NFE AF= 0.00882 (600/68006). AF 95% confidence interval is 0.00824. There are 3 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 752 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5 linkuse as main transcript	c.1565C>G	p.Pro522Arg	missense_variant	17/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6 linkuse as main transcript	c.1565C>G	p.Pro522Arg	missense_variant	17/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00495

AC:

753

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00882

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00518

AC:

1291

AN:

249084

Hom.:

AF XY:

0.00525

AC XY:

709

AN XY:

135126

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00360

Gnomad ASJ exome

AF:

0.00807

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000459

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00876

Gnomad OTH exome

AF:

0.00496

GnomAD4 exome

AF:

0.00692

AC:

10118

AN:

1461312

Hom.:

Cov.:

AF XY:

0.00675

AC XY:

4909

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00401

Gnomad4 ASJ exome

AF:

0.00831

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000604

Gnomad4 FIN exome

AF:

0.00146

Gnomad4 NFE exome

AF:

0.00826

Gnomad4 OTH exome

AF:

0.00563

GnomAD4 genome

AF:

0.00494

AC:

752

AN:

152236

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00882

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00745

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.000789

AC:

ESP6500EA

AF:

0.00888

AC:

ExAC

AF:

0.00504

AC:

609

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00993

EpiControl

AF:

0.00943

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PLCG2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 27, 2017	- -

PLCG2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cold autoinflammatory syndrome 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

Sift4G

Benign

0.52

T;T

Polyphen

0.0

B;.

Vest4

0.20

MVP

0.41

MPC

0.29

ClinPred

0.0084

GERP RS

4.8

Varity_R

0.050

gMVP

0.66

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