rs201803492

chr16-81923489-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_002661.5(PLCG2):c.2312A>G(p.Gln771Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000336 in 1,607,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19220358).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000138 (21/152318) while in subpopulation AFR AF= 0.000433 (18/41574). AF 95% confidence interval is 0.000279. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.2312A>G	p.Gln771Arg	missense_variant	22/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.2312A>G	p.Gln771Arg	missense_variant	22/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000731 AC: 18 AN: 246164 Hom.: 0 AF XY: 0.0000373 AC XY: 5 AN XY: 133908

Gnomad AFR exome AF: 0.000263

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000227 AC: 33 AN: 1455252 Hom.: 0 Cov.: 29 AF XY: 0.0000207 AC XY: 15 AN XY: 724060

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74480

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000211 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.000521 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cold autoinflammatory syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 771 of the PLCG2 protein (p.Gln771Arg). This variant is present in population databases (rs201803492, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PLCG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 540099). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	0.034
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.25	T;T
Polyphen		0.34	B;.
Vest4		0.52
MVP		0.55
MPC		0.40
ClinPred		0.045	T
GERP RS		5.5
Varity_R		0.17
gMVP		0.59

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

Other links and lift over

dbSNP: rs201803492; hg19: chr16-81957094;