Genetic Variant PLCG2:p.Leu845Phe (chr16-81928578-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_002661.5(PLCG2):c.2535A>T(p.Leu845Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L845S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.881

Publications

68 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
familial cold autoinflammatory syndrome 3
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

PLCG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-81928577-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1693266.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002661.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCG2	NM_002661.5	MANE Select	c.2535A>T	p.Leu845Phe	missense	Exon 24 of 33	NP_002652.2
PLCG2	NM_001425749.1		c.2535A>T	p.Leu845Phe	missense	Exon 25 of 34	NP_001412678.1
PLCG2	NM_001425750.1		c.2535A>T	p.Leu845Phe	missense	Exon 24 of 33	NP_001412679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.2535A>T	p.Leu845Phe	missense	Exon 24 of 33	ENSP00000482457.1
PLCG2	ENST00000902427.1		c.2688A>T	p.Leu896Phe	missense	Exon 25 of 34	ENSP00000572486.1
PLCG2	ENST00000565054.7	TSL:5	c.2535A>T	p.Leu845Phe	missense	Exon 25 of 34	ENSP00000520638.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.1

PhyloP100

0.88

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.44

Sift

Benign

0.047

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.70

MutPred

0.46

Loss of catalytic residue at L845 (P = 0.0079)

MVP

0.72

MPC

0.99

ClinPred

0.96

GERP RS

1.9

Varity_R

0.65

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over