rs772451566

Variant names:

• chr16-81869281-C-T
• rs772451566
• NM_002661.5:c.547C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002661.5(PLCG2):​c.547C>T​(p.Leu183Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.24

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.547C>T	p.Leu183Phe	missense_variant	Exon 6 of 33	ENST00000564138.6	NP_002652.2
PLCG2	NM_001425749.1	c.547C>T	p.Leu183Phe	missense_variant	Exon 7 of 34		NP_001412678.1
PLCG2	NM_001425750.1	c.547C>T	p.Leu183Phe	missense_variant	Exon 6 of 33		NP_001412679.1
PLCG2	NM_001425751.1	c.547C>T	p.Leu183Phe	missense_variant	Exon 7 of 34		NP_001412680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.547C>T	p.Leu183Phe	missense_variant	Exon 6 of 33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249516 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460446 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cold autoinflammatory syndrome 3;C3553961:Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation Uncertain:1

Dec 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cold autoinflammatory syndrome 3 Uncertain:1

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 183 of the PLCG2 protein (p.Leu183Phe). This variant is present in population databases (rs772451566, gnomAD 0.003%). 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: 540096). 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	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	.;D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.56
MutPred		0.53		Gain of methylation at K184 (P = 0.1624);Gain of methylation at K184 (P = 0.1624);
MVP		0.61
MPC		0.094
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.57
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs772451566; hg19: chr16-81902886; COSMIC: COSV63877969; COSMIC: COSV63877969;