16-81900760-C-G

Position:

• chr16-81900760-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002661.5(PLCG2):​c.1342C>G​(p.Arg448Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.43

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCG2	NM_002661.5	c.1342C>G	p.Arg448Gly	missense_variant	14/33	ENST00000564138.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCG2	ENST00000564138.6	c.1342C>G	p.Arg448Gly	missense_variant	14/33	1	NM_002661.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.1	.;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.55	P;.
Vest4		0.63
MutPred		0.57		Loss of MoRF binding (P = 0.0547);Loss of MoRF binding (P = 0.0547);
MVP		0.70
MPC		0.51
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.71
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-81934365;