rs75472618

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.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. 13/20 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:7

Conservation

PhyloP100: 2.36

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=0.0071565807).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5 linkuse as main transcript	c.1712A>G	p.Asn571Ser	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.1712A>G	p.Asn571Ser	missense_variant	17/33	1	NM_002661.5	P1

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

GnomAD3 exomes

AF:

0.00675

AC:

1673

AN:

248008

Hom.:

AF XY:

0.00661

AC XY:

889

AN XY:

134514

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 SAS exome

AF:

0.000987

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

Gnomad4 AFR exome

AF:

0.00880

Gnomad4 AMR exome

AF:

0.0128

Gnomad4 ASJ exome

AF:

0.0186

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.000993

Gnomad4 NFE exome

AF:

0.00643

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.00784

AC:

1193

AN:

152226

Hom.:

Cov.:

AF XY:

0.00720

AC XY:

536

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00864

Gnomad4 AMR

AF:

0.0125

Gnomad4 ASJ

AF:

0.0170

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00757

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.00751

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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 24, 2022

- -

Familial cold autoinflammatory syndrome 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0072

T;T

MetaSVM

Uncertain

-0.0044

MutationAssessor

Benign

0.33

N;.

MutationTaster

Benign

0.62

PrimateAI

Benign

0.39

Sift4G

Uncertain

0.035

D;D

Polyphen

0.0010

B;.

Vest4

0.36

MVP

0.72

MPC

0.22

ClinPred

0.021

GERP RS

4.8

Varity_R

0.13

gMVP

0.36

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

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