Genetic Variant NM_002661.5:c.3109G>C (chr16-81937814-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002661.5(PLCG2):c.3109G>C(p.Val1037Leu) variant causes a missense change. 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. V1037I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PLCG2
NM_002661.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.32

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.3109G>C	p.Val1037Leu	missense	Exon 28 of 33	NP_002652.2
PLCG2	NM_001425749.1		c.3109G>C	p.Val1037Leu	missense	Exon 29 of 34	NP_001412678.1
PLCG2	NM_001425750.1		c.3109G>C	p.Val1037Leu	missense	Exon 28 of 33	NP_001412679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCG2	ENST00000564138.6	TSL:1 MANE Select	c.3109G>C	p.Val1037Leu	missense	Exon 28 of 33	ENSP00000482457.1
PLCG2	ENST00000565054.7	TSL:5	c.3109G>C	p.Val1037Leu	missense	Exon 29 of 34	ENSP00000520638.1
PLCG2	ENST00000697580.2		c.3109G>C	p.Val1037Leu	missense	Exon 28 of 33	ENSP00000520637.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.6

PhyloP100

5.3

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.36

Sift

Benign

0.10

Sift4G

Benign

0.16

Polyphen

0.048

Vest4

0.64

MutPred

0.53

Gain of sheet (P = 0.1208)

MVP

0.95

MPC

0.38

ClinPred

0.66

GERP RS

5.4

Varity_R

0.28

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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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