16-81912633-G-T

Position:

• chr16-81912633-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002661.5(PLCG2):​c.1971G>T​(p.Glu657Asp) 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.1971G>T	p.Glu657Asp	missense_variant	19/33	ENST00000564138.6	NP_002652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.1971G>T	p.Glu657Asp	missense_variant	19/33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.3	.;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.021	.;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.095	B;.
Vest4		0.81
MutPred		0.80		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.92
MPC		0.31
ClinPred		0.92	D
GERP RS		2.9
Varity_R		0.29
gMVP		0.80

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: rs758439876; hg19: chr16-81946238; COSMIC: COSV100842564;