rs397514562

Positions:

• chr16-81919549-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002661.5(PLCG2):​c.2120C>A​(p.Ser707Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCG2 NM_002661.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.50

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 16-81919549-C-A is Pathogenic according to our data. Variant chr16-81919549-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 39696.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-81919549-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCG2	NM_002661.5	c.2120C>A	p.Ser707Tyr	missense_variant	20/33	ENST00000564138.6	NP_002652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCG2	ENST00000564138.6	c.2120C>A	p.Ser707Tyr	missense_variant	20/33	1	NM_002661.5	ENSP00000482457.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 05, 2012

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	.;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.61		Loss of MoRF binding (P = 0.1167);Loss of MoRF binding (P = 0.1167);
MVP		0.77
MPC		1.1
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.65
gMVP		0.73

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: rs397514562; hg19: chr16-81953154;